Strong and consistent evidence exists that physical activity reduces breast cancer risk by 10-25 %, and several proposed biologic mechanisms have now been investigated in randomized, controlled, exercise intervention trials. Leading hypothesized mechanisms relating to postmenopausal breast cancer include adiposity, endogenous sex hormones, insulin resistance, and chronic low-grade inflammation. In addition, other pathways are emerging as potentially important, including those involving oxidative stress and telomere length, global DNA hypomethylation, immune function, and vitamin D exposure. Recent exercise trials in overweight/obese postmenopausal women implicate weight loss as a mechanism whereby exercise induces favorable changes in circulating estradiol levels and other biomarkers as well. Still it is plausible that some exercise-induced biomarker changes do not require loss of body fat, whereas others depend on abdominal fat loss. We highlight the latest findings from randomized, controlled trials of healthy postmenopausal women, relating exercise to proposed biomarkers for postmenopausal breast cancer risk. We also update our biologic model that relates physical activity to breast cancer by incorporating newly hypothesized biomarkers. Our goal is to guide future clinical and mechanistic research surrounding physical activity and postmenopausal breast cancer prevention. The focus of this review will be on healthy women in whom biomarker profiles and the types and effects of prescribed exercise may differ from breast cancer survivors. Biomarker studies in breast cancer survivors are reviewed elsewhere •, 13.To simplify our discussion of the existing epidemiologic evidence, we have classified proposed biomarkers of breast cancer risk as “convincing” or “hypothesized.” Our classification of estrogens and adiposity as convincing biomarkers is based on the relatively strong and consistent body of epidemiologic evidence relating these markers to postmenopausal breast cancer risk. We summarize that evidence and describe in more detail the effects of exercise on estrogen levels  and adiposity (citing recent reviews and large RCTs), specifically in postmenopausal women. We then provide a high-level overview of other, hypothesized biomarkers of postmenopausal breast cancer risk and possible relations with exercise.2) and trained athletes.In September 2013, we searched the published literature (PubMed-NIH) for RCTs that studied the impact of exercise on estrogens. In brief, we identified all RCTs of long-term exercise (≥4 weeks) that compared exercise-only to a nonexercise control group in healthy postmenopausal women. Studies exclusive to hormone replacement therapy users were excluded as were studies in morbidly obese women  are related to an increased risk of postmenopausal breast cancer . In addiA total of nine exercise-only RCTs in postmenopausal women that studied changes in estrogen-related biomarkers for breast cancer were identified in our systematic review of published literature Table . The numstatistically significant differences between exercise and control groups with respect to change in total estradiol  and perhaps IL-6 [2max), but revealed no difference with respect to CRP change in exercisers versus controls over 6 months [RCT findings overall imply that exercise aps IL-6 •, 68• inaps IL-6 –71, but aps IL-6 , and in aps IL-6 . The Dos6 months . Six RCT50 , 51, • and per6 months , 73. Fur6 months , 69, 70 Weight loss is a plausible mediator of exercise-induced adipokine changes given strong biologic rationale and a growing body of RCT evidence, particularly for leptin. The NEW trial, for example, demonstrated up to a 53 % average decrease in leptin concentrations in subgroups with ≥10 % weight loss, which far exceeded changes in subgroups with <5 % weight loss  •. The meEvading immunological destruction is an emerging hallmark of cancer and a diminished competence of the immune response is a recognized predictor of cancer risk; however, there is currently no consensus on which immune biomarkers are causally related to cancer risk , 75.in vitro natural killer cell cytotoxicity, T-lymphocyte proliferative response to stimulation, or the relative proportion of immune cell counts  [Physical activity might impede carcinogenesis by moderating the innate and adaptive immune systems  and, thur cells) .Oxidative stress results from an imbalance of increased systemic reactive oxygen species (ROS) production and/or reduced antioxidant capacity, including the ability to neutralize reactive intermediates and repair subsequent damage. It is hypothesized to play a central role in breast carcinogenesis  and in c2-isoprostane levels in exercisers compared to controls, with a more pronounced statistically significant reduction in exercisers who increased their physical fitness by >15 %; this effect occurred independent of obesity status [As part of a favourable biological adaptive response, regular exercise enhances antioxidant and oxidative damage repairing enzyme capacity and may subsequently reduce oxidative damage . The epiy status . RCTs ofy status  and resiy status  also shoy status •, nor diy status .The methylation of DNA is recognized as a key epigenetic mechanism in the regulation of gene expression and chromosomal stability. Global DNA hypomethylation in peripheral blood leukocytes represents a postulated biomarker for cancer risk  and epid3 when UV-B exposure is sufficiently high. Another mechanism involves body composition, because the metabolite 25-hydroxyvitamin D (25(OH)D), the most common serum indicator of vitamin D status, might sequester in body fat [p-trend = 0.002) [p-trend = 0.005), and in multivariable models, weight loss >10 % was identified as a significant predictor of 25(OH)D change [A protective, inverse association between vitamin D exposure and postmenopausal breast cancer risk is becoming increasingly clear , 98. Forbody fat . Evidenc= 0.002) •. FurtheD change .Figure Adiposity change could play a mediating role for any of the biomarkers proposed in our model, or for some biomarkers, physical activity might act independently. The state of being overweight or obese also could modify the effects of physical activity on other biomarkers. Distinguishing the effects of “fat and fit” on breast cancer biomarkers is methodologically challenging and of interest •, 107. FWhile considerable advances have been made in our understanding of the biologic mechanisms relating physical activity to postmenopausal breast cancer risk, opportunity remains for future research. To begin, several newly hypothesized biologic pathways require further study to better understand their etiologic roles in postmenopausal breast cancer and hence, their suitability as biomarkers. Second, although our list of proposed biomarkers is fairly comprehensive, encompassing our own areas of research, additional biomarkers can be considered for our model, including, for example, those related to DNA repair mechanisms, additional epigenetic indicators, other adipokines, and anti-inflammatory cytokines. Several of these mechanisms may be more intensive to measure than what has been done previously, such as genomic alterations, and may require a tissue-specific approach. Hypothesized biomarkers also could be removed from the model as data becomes available; e.g., exercise-only trials in older women thus far have not produced changes in circulating adiponectin, TNF-α, or IL-6 levels. Third, biomarker-exercise RCTs could be analyzed using a systems epidemiology approach , quantifOne recently completed, noteworthy study is the Breast Cancer and Exercise Trial in Alberta . This trial, comprising 400 postmenopausal, previously inactive women who were randomized to undertake either 150 or 300 minutes per week of aerobic exercise for 1 year, was designed specifically to determine the optimal activity dose for lowering postmenopausal breast cancer risk. In secondary analyses of the ALPHA trial data, higher exercise duration was associated with desirable changes in adiposity and circulating sex steroid hormone levels, HOMA-IR, leptin, and CRP levels, with the greatest benefit observed for women undertaking >150 minutes per week  or >225 Evidence from randomized exercise trials in healthy, overweight and obese postmenopausal women implies that moderate-vigorous aerobic exercise prescriptions of 150–225 minutes per week over 12 months can lower estradiol levels by approximately 5-10 % on average, primarily through total body weight loss. Yet, there is biologic plausibility that some exercise-induced biomarker changes do not require loss of body fat, whereas others depend on abdominal fat loss. The preventive effect of exercise is probably the culmination of numerous interrelated biomarker changes that, when combined, act additively or synergistically to impede carcinogenesis in the breast. The level of physical activity required to induce these changes could be higher than the minimum level currently advised for cancer prevention and might depend on individual factors, e.g., genetic constitution. Identifying a physical activity prescription that produces clinically meaningful changes in key biomarkers and subgroups of women who would benefit the most from physical activity is a priority for future research. These recommendations will be used to inform prevention strategies for breast cancer after menopause.


Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women.We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) for cause-specific mortality were calculated using Cox proportional hazards regression.Seventeen percent  of breast cancer survivors (mean age at diagnosis = 63.5) reported pre-diagnosis TAHBSO. During follow-up (mean = 9.5 years), 2,856 deaths occurred, including 1,060 breast cancer deaths and 459 CVD deaths. Breast cancer deaths occurred a median of 5.1 years after diagnosis; CVD deaths occurred further from diagnosis (median = 9.7 years). Women who reported pre-diagnosis TAHBSO had a 16% decrease in all-cause mortality  compared to those with an intact uterus and ovaries. This overall decrease reflected a 27% lower breast cancer mortality among women who never used postmenopausal hormones  and 43% lower CVD risk among women who reported using estrogen  after TAHBSO.Information on prior TAHBSO and estrogen use can inform risk of death from both breast cancer and cardiovascular disease among breast cancer survivors. BRCA1/2 mutation status [With a growing population of >2.7 million breast cancer survivors in the United States , identifn status . Howevern status ,12-15. Tn status ,16-18.In the United States, total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) is often performed for benign conditions such as uterine fibroids; an estimated 15% of US women have their uterus and ovaries removed by age 60 ,20. IdenThis analysis was performed with data from the Collaborative Breast Cancer Study Cohort ,21,22. CStudy participants were female residents of Wisconsin, Massachusetts, or New Hampshire with an incident invasive breast cancer reported to each state’s cancer registry during the study enrollment years. Eligibility was limited to women with listed telephone numbers, driver’s licenses (if younger than 65 years), and registry-reported dates of diagnosis. Women ages 50 to 79 were eligible in the first study (1992 to 1995); and ages 20 to 69 in subsequent studies . During 1992 to 2001 participants were enrolled in Wisconsin, Massachusetts, and New Hampshire; in 2001 to 2007 women were enrolled in Wisconsin only. Across the four studies, 21,713 eligible participants were identified. Physicians refused contact with 359 (1.7%), 743 (3.4%) were deceased, 624 (2.9%) could not be located and 2,794 (12.9%) refused to participate. Therefore, 17,193 (79.2%) eligible breast cancer survivors were interviewed. Thirty-eight interviews were considered unreliable by the interviewers, leaving 17,155 interviews available for analysis.In each study, participants completed a 40-minute structured telephone interview that elicited detailed information on lifestyle and demographic factors, postmenopausal hormone use, and personal and family medical history. Study participants reported whether they had surgery to remove the uterus or ovaries, the type of surgery , and age at surgery. Participants were asked a standard history of postmenopausal hormone use including formulation, route of administration, age started, frequency of each episode of use, total duration, and time since last use.2 during the one- to five-year period prior to breast cancer diagnosis.In three of the four pooled studies , menopause was defined as the absence of menses for six consecutive months not attributable to surgery, chemotherapy, radiation, or other reasons. In the most recent study (2004 to 2007), menopause was defined as 12 consecutive months without menses. In all studies, women who reported bilateral oophorectomy prior to breast cancer diagnosis were categorized as postmenopausal. BMI was calculated as weight (kg)/tallest adult height (m)Vital status information, including date and underlying cause of death, was collected through December 31, 2009 through linkage with the National Death Index. Cause of death was categorized according to the International Classification of Disease (ICD-10) code as breast cancer-specific mortality (C50), cardiovascular (CVD) mortality , stroke mortality (I60 to I69), or all-cause mortality .For consistency in ages at enrollment across studies, this pooled analysis was limited to women age 50 and older at breast cancer diagnosis . We further excluded women who were premenopausal at diagnosis  or had unknown menopausal status (N = 620), or who had a previous history of cancer (except non-melanoma skin cancer) (N = 614). Ninety-three records from women with discordant ages at bilateral oophorectomy and hysterectomy and 41 records with missing ages for both procedures were excluded. To exclude gynecologic surgeries performed as part of breast cancer treatment, 84 women who reported bilateral oophorectomy or hysterectomy at the same age or after breast cancer diagnosis were excluded. Six records were excluded based on partial interview completion. After these exclusions were applied, 10,443 women were eligible for analysis. Among the eligible breast cancer survivors, 1,778 (17.0%) reported having a prior TAHBSO and 6,913 (66.2%) reported having an intact uterus and ovaries at breast cancer diagnosis; therefore, records from 8,691 breast cancer survivors contributed to this analysis. The remaining 1,752 records included 1,641 women who reported hysterectomy alone or unilateral oophorectomy with or without hysterectomy, and 111 women with missing information on previous gynecologic surgery. On average, women were interviewed 1.3 years (standard deviation (SD) = 0.5; range: 0.2 to 4.9) after breast cancer diagnosis.All mortality comparisons were made relative to women who reported having an intact uterus and ovaries and never using postmenopausal hormones at breast cancer diagnosis. Kaplan Meier curves were produced to display mortality curves; formal statistical comparison of the difference in slopes was conducted with log rank tests . For surA priori, final estimates were adjusted for stage of diagnosis, state, study enrollment years, age at diagnosis, BMI one to five years before breast cancer diagnosis, smoking status at breast cancer diagnosis, and family history of breast cancer as potential confounders. P values ≤0.05 were considered to be statistically significant. All statistical analyses were performed with Stata 12 software .Cox proportional hazards regression was used to calculate multivariate hazard ratios (HR) for all-cause mortality. The Fine and Gray method was used to fit proportional cumulative incidence-associated subhazards regression models for breast cancer and CVD-specific mortality to account for non-breast and non-CVD disease deaths as competing events ,26. A prAcross the four studies, the majority of participants were enrolled in Wisconsin (69%) and were diagnosed with local invasive disease (64%). We conducted sensitivity analyses to evaluate whether inclusion of participants in Massachusetts and New Hampshire or those with regional or distant disease influenced our results.A total of 2,856 deaths occurred during 82,201 person-years  contributed by 8,691 women. The greatest proportion (37.1%) of deaths were due to breast cancer , followed by coronary heart disease  and stroke .Study participant characteristics according to gynecologic surgery status are presented in Table TAHBSO was associated with a 16% decrease in mortality from all causes : 0.76, 0.92). All-cause mortality did not appear to vary according to age at surgery. The inverse association between pre-diagnosis TAHBSO and all-cause mortality was of greater magnitude among women who reported using estrogen therapy  compared to no estrogen use  . No variation was observed according to age at surgery. When evaluated according to estrogen use, decreased breast cancer mortality risk was observed among women who reported TAHBSO and never used hormones  but not among women who used unopposed estrogens  . In analyses stratified according to age at diagnosis, TAHBSO was associated with statistically significant reductions in breast cancer mortality only among women ages 50 to 64 at diagnosis  Table .Overall, the association between TAHBSO and risk of death due to CVD was not statistically significant  in multivariate competing-risk regression models. When evaluated according to age at surgery, TAHBSO at ages ≤45 years was not related to CVD mortality , but decreased CVD mortality was observed among women who reported TAHBSO at older ages . Women who reported TAHBSO and estrogen therapy use had a 43% decrease in CVD mortality ; and those who reported at least 10 years of estrogen use had an estimated 55% reduction in CVD mortality . Conversely, women who reported TAHBSO and did not use estrogen had a non-statistically significant 19% increase in CVD mortality risk  . Sample sizes were insufficient to calculate fully adjusted HRs for CVD mortality among women ages 50 to 64 at diagnosis, estimates in this group are adjusted for study enrollment years, age and stage at diagnosis only. A 68% decrease in CVD mortality was estimated among women ages 50 to 64 at diagnosis who reported previous TAHBSO and estrogen use . Among women who were ≥65 at diagnosis, we observed a 35% decrease in CVD mortality associated with TAHBSO and estrogen use   or those with local disease , our findings were essentially unchanged compared to the overall analysis.In this study, postmenopausal women who had a hysterectomy with bilateral oophorectomy prior to breast cancer diagnosis had an estimated 16% reduction in all-cause mortality and 24% decrease in breast cancer mortality compared to women who had an intact uterus and never used hormones, irrespective of age at surgery. Cause-specific mortality associations differed according to post-surgical estrogen use. Breast cancer mortality was lowest among those who did not use estrogens after surgery, while cardiovascular disease and all-cause mortality were lowest among estrogen users. These patterns were more apparent among five-year breast cancer survivors compared to women who were within five years of a breast cancer diagnosis. These findings indicate that prior oophorectomy and estrogen use can impact cause of death among breast cancer survivors.Results from historical  and recePrevious studies have suggested that use of estrogen therapy after TAHBSO can mitigate the potential increased risk of CVD associated with early surgical menopause ,14,16. WLimitations to this analysis include potential misclassification of exposure based on self-reported information. However, our confidence in these data is strengthened by the high reliability of the study questionnaire. In a sequential sample of 195 women without breast cancer who were re-interviewed after an average of 3.5 months, hysterectomy and oophorectomy status were highly reproducible  . AlthougIn the Women’s Contraceptive and Reproductive Experiences case-control study, bilateral oophorectomy was associated with stronger reductions in the incidence of estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancers  compared to ER-/PR- tumors  . In our Our exposure assessment was based on a single interview conducted approximately one year after breast cancer diagnosis. Some study participants may have undergone TAHBSO after this time; these surgeries would have been performed after menopause and would likely exert a lesser effect on mortality risk, although intact ovaries continue to produce small amounts of androgens after menopause and could influence chronic disease risk ,43. The This analysis provides evidence of a beneficial effect of pre-diagnosis TAHBSO on overall mortality in a large, population-based cohort of breast cancer survivors. Given that an estimated 15% of US women in the general population undergo elective bilateral oophorectomy by age 60 , and breBMI: Body mass index; CI: Confidence interval; CVD: Cardiovascular disease; ER: Estrogen receptor; HR: Hazard ratio; PR: Progesterone receptor; SD: Standard deviation; TAHBSO: Total abdominal hysterectomy bilateral salpingo-oophorectomy.The authors declare that they have no competing interests.This analysis was conceived and proposed by HN and KV. HN, ATD, PN, KE, LT, JH, and KV contributed substantially to the design and interpretation of data. Data analysis was performed by HN and JH. HN, ATD, PN, KE, LT, JH, and KV were involved in revising the manuscript for intellectual content and gave final approval for publication.


Zinc is a micronutrient, which is essential for human health, playing role as a cofactor of enzymes such as dehydrogenases, peptidases and component of zinc finger domains. In organism zinc is involved in metabolic pathways, immune processes, maintaining ion balance between other elements. Recently, it has been reported that zinc may play role in chemoprevention, and its level may be associated with cancer risk.The aim of this study was to analyze possible association between serum zinc level and breast cancer risk in BRCA1 mutation carriers and noncarriers.The studies have been performed on 3 independent groups: (1) 119 unselected breast cancer patients matched 1:1 with 119 unaffected controls (carriers of BRCA1 mutation have been excluded), (2) 99 breast cancer cases  and 198 matched 1:2 unaffected controls, (3):27 breast cancer cases (serum collected 1-2 years before diagnosis) and 53 controls matched 1:2. All individuals in groups (2) and (3) were carriers of BRCA1 mutation.Zinc level in serum was measured by inductively coupled plasma mass spectrometry (ICP-MS) using Elan DRC-e ICP-Mass Spectrometer, Perkin Elmer.In the group of unselected breast cancer patients, individuals with zinc level 759,64-985,24 μg/L had a lower risk of breast cancer than those with zinc level 107,18–759,64 μg/L. Observation was statistically insignificant .In group of BRCA1 carriers, in which serum was collected at the moment of diagnosis, individuals with zinc level 692,48 – 756,01 μg/L had significantly lower risk of breast cancer than those with zinc level 218,89 – 692,48 μg/L .In the group of BRCA1 carriers, in which serum was collected 1-2 years before diagnosis, individuals with zinc level >831,35) had significantly lower risk of breast cancer .We observed that serum zinc level is associated with breast cancer risk in BRCA1 carriers and noncarriers. Analysis of serum zinc concentration revealed tendency to increased risk of breast cancer for unselected breast cancers and BRCA1 carriers with zinc level <750±50 μg/L. Probably high zinc level reduces cancer risk especially in BRCA1 carriers, but these results should be confirmed in larger cohorts.


The effect of antioxidants on breast cancer is still controversial. Our objective was to assess the association between antioxidants and breast cancer risk in a large population-based case-control study.The study population included 2,362 cases with pathologically confirmed incident breast cancer  and 2,462 controls in Canada. Intakes of antioxidants from diet and from supplementation as well as other potential risk factors for breast cancer were collected by a self-reported questionnaire.Compared with subjects with no supplementation, 10 years or longer supplementation of zinc had multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) of 0.46 (0.25-0.85) for premenopausal women, while supplementation of 10 years or longer of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc had multivariable-adjusted ORs (95% CIs) of 0.74 , 0.58 , 0.79 (0.63-0.99), 0.75 , and 0.47 (0.28-0.78), respectively, for postmenopausal women. No significant effect of antioxidants from dietary sources  or from supplementation less than 10 years was observed.This study suggests that supplementation of zinc in premenopausal women, and supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer. However, we were unable to determine the overall effect of total dose or intake from both diet and supplement. Breast cancer is the most common cancer and the second leading cause of cancer-related death among Canadian women . AccordiRecently, antioxidants such as vitamin A and its precursor , vitamins C, E, and selenium, have drawn a lot of attention to the scientists and the public alike ,3. They Although there is considerable evidence of anticancer effect of antioxidants from cell culture and animal studies, the results from observational studies and intervention trials are inconsistent ,12,13. AThis study was based on data collected by the National Enhanced Cancer Surveillance System (NECSS). The details of NECSS, including the study design, study population, and data collection strategies, have been published elsewhere , and areInternational Classification of Diseases for Oncology, Second Edition (ICD-O-2). The cancer registries tried to identify cases as soon as possible after diagnosis to reduce the loss of subjects caused by severe illness and death. Provincial cancer registries identified 3386 women with breast cancer. Physician consent to contact the cases was requested for 3248 cases. Seventy-four women had died at the time of the physician request, and the physician refused consent for another 224 cases. Questionnaires were sent to 3013 cases and 2982 cases were contacted. Completed questionnaires were received from 2362 cases, representing 78.4% of cases who were sent questionnaires and 69.7% of those ascertained.The population-based provincial cancer registries identified breast cancer cases through a review of pathology reports. All cases were pathologically confirmed incident breast cancer patients, newly diagnosed between 1994 and 1997 in the eight participating provinces. Breast cancer was defined as C50 according to the Control subjects were women with no prior diagnosis of cancer and residents of the participating provinces. In NECSS, frequency matching to the overall case group (19 types of cancers) was used to select population controls with similar age and sex distribution, so that there would be at least one control for every case within each sex and 5-year age group for any specific cancer site within each province. The sampling strategy for control selection varied by province, depending on data availability, data quality (completeness and timeliness) and the confidentiality restrictions of provincial databases. Prince Edward Island, Nova Scotia, Manitoba, Saskatchewan, and British Columbia used provincial health insurance plans to get a random sample of the provincial population stratified by age group and sex. More than 95% Canadians are covered by these public plans, and individuals are excluded only if covered through other federal plans. In Ontario, the Provincial Ministry of Finance Property Assessment databases, which are intended to include all residents of the province and are updated monthly, were used to obtain a stratified random sample. Newfoundland and Alberta used similar random digit dialling protocols to obtain population samples.Questionnaires were mailed to 3847 women selected as potential controls. For 286 of these women 7.4%, the mailed questionnaires were returned to the registry indicating a wrong or old address, and no updated address could be found through publicly available sources. In total, 2492 women completed and returned the questionnaire, representing 71.3% of those contacted and 64.8% of these ascertained.The provincial registries collected data by self-administered questionnaires, with telephone follow-up when necessary for clarification and completeness. The questionnaires were designed to obtain detailed data on potential risk factors for cancers. The questionnaires collected information on education, average family income over the last 5 years, marital status, ethnic group, smoking, height, weight, physical activity, alcohol consumption, diet (69-item food frequency questions) 2 years before interview, and length of vitamin and mineral supplements for the past 20 years. Questionnaires also gathered information about menstrual and reproductive history and residential history.The diet component of the questionnaire used a 69-item food frequency instrument to collect information on diet from 2 years before the interview date. The design of the diet component of the questionnaire was based on two validated instruments: the National Cancer Institute's Block Questionnaire , and theA commonly used portion or serving size was specified for each food or beverage item. Respondents indicated the usual frequency of consumption of that portion size for each food item by selecting one of nine possible categories: 0 or < 1 per month, 1 to 3 per month, 1 per week, 2 to 4 per week, 5 to 6 per week, 1 per day, 2 to 3 per day, 4 to 5 per day, or ≥ 6 per day. The weekly consumption of each food item was then calculated as the product of frequency and serving size. The nutrient content of foods was determined using food composition data from the Canadian Nutrient Guide and Canadian Nutrient File ). The toThe questionnaire also collected information regarding vitamin or mineral supplement use (frequency and length) during the past 20 years. Respondents were asked how often  and for how many years in total they had taken each of the 10 vitamins and mineral supplements . The ten vitamins and minerals are multiple vitamins, vitamin A, vitamin C, vitamin E, B-complex vitamins, beta-carotene, calcium, iron, zinc, and selenium.The questionnaire gathered information on recreational physical activity 2 years before interview. Respondents were asked in which seasons, how often and how long per session, on average, they participated in each of the 12 most common types of leisure-time physical activity in Canada. Individual activities included walking for exercise, bowling or curling, social dancing, gardening or yard work, golf, home exercise or exercise class, bicycling, jogging or running, racquet sports, swimming or water exercise, skiing or skating, and other strenuous exercise. Respondents indicated their usual frequency of participating in each of the above activities by choosing one of the following categories: never, less than once per month, 1 - 3 times per month, 1 - 2 times per week, 3 - 6 times per week or every day.As a measure of overweight and obesity, body mass index (BMI) was calculated as the reference weight in kilograms (2 years before interview) divided by height in meters squared.We estimated the risk of breast cancer associated with intake of dietary antioxidants  and with years of supplementation of antioxidants  based on odds ratios (ORs) and corresponding 95% confidence intervals (CIs), using unconditional logistic regression with the software package SAS . For antioxidants from dietary intake, exposure variables were categorized into quartiles based on the distribution of the variables in the control population, with the lowest quartile as the reference. For antioxidants from supplementation, exposure variables were categorized by length of supplementation . Total intake of antioxidants was examined in following way: high  versus low (lower than median) intake of antioxidant from diet only, high (≥ 10 years) versus low (< 10 years) intake from supplementation only, and high intake from both diet  and supplementation (≥ 10 years) versus low intake (from either sources). The analysis was performed for premenopausal and postmenopausal breast cancers separately. We conducted tests for trends for all models of categorized data by treating the different categories as a single ordinal variable.Because cases and controls were not directly matched, the methods for identifying cases and controls varied by province; and, because age is associated with breast cancer risk, all logistic regression analyses were controlled for province of residence and age to remove the impact of any uneven distribution of these factors between cases and controls. We used the change-in-point-estimate approach to assess the potential confounding effect of a wide range of factors, including age, family income, educational level, alcohol consumption, smoking, BMI, total calorie intake, recreational physical activity level, menopausal status, and number of live births. We retained variables in the final models that are considered biologically important if their inclusion changed the odds ratio estimate appreciably, regardless of the statistical significance. We adjusted the final multivariate models for age , province of residence, education , number of live births , age at menarche , alcohol consumption , pack-years of smoking (continuous) and total calorie intake . For postmenopausal women, the models were also adjusted for BMI and recreational physical activity. Mutual adjustments were done for analyses on antioxidants from dietary source and from supplementation.Data from 2,362 breast cancer cases  and 2,462 controls were available for analysis.Table Table Table Table Table Our large population based study indicated that supplementations of 10 years or longer with zinc were associated with statistically significant reductions in premenopausal breast cancer risk. For postmenopausal women, supplementations of 10 years or longer of multiple vitamins, beta-carotene, vitamin C, vitamin E and zinc were associated with statistically significant reductions for breast cancer risk. No significant difference was observed in breast cancer risk, either premenopausal or postmenopausal, across different levels of antioxidants from dietary sources, nor was there a significant effect of supplementation shorter than 10 years. With the ability to draw a national sample, our study is amongst the largest in the field. We have also been able to adjust for a number of risk factors known to be related to breast cancer such as BMI, energy intake, and physical activity. However, this study could not determine the overall effect of total dose or intake of antioxidants from both diet and supplement.Carotenoids (precursor of vitamin A) include alpha-carotene, beta-carotene, lutein, lycopene, and beta-cryptoxanthin. Higher dietary intakes and blood concentrations of carotenoids, including beta-carotene, have been shown to reduce breast cancer risk, but the results are not entirely consistent ,19. A suZinc is involved with metallothionine synthesis, which is believed to inhibit free radical production . Zinc suAlthough studies in cell cultures and animals showed that vitamin E and C prevent transformation of normal cells to cancer cells and selectively induce apoptosis in cancer cells, the results of epidemiologic studies have been inconsistent . The revBecause of differences in study population, study design, and nutritional assessment, it is rather difficult to reconcile results from different studies. Our study did not find any association between any antioxidant from dietary sources and breast cancer risk, or an effect of supplementation shorter than 10 years on breast cancer risk, for both premenopausal and postmenopausal cases. It is difficult to measure nutrients from dietary intake by case control studies. Although the response rate was 69.7% for breast cancer cases, selection (inclusion) of cases was not related to exposure status (i.e. antioxidant intake), therefore, selection bias is unlikely to occur. Recall bias, inherent in all case-control design, is possible because cases might bias their responses to questions on diet after a few months of cancer diagnosis. The possibility that such a bias was introduced into our study was reduced by including many questions on other exposures, such as socio-demographic factors, physical activity, weight, smoking history, employment history and residential history and by not placing any particular emphasis on diet in the questionnaire. Although we used a widely validated questionnaire, measurement error of dietary intakes, for example, self-reports of long-term dietary supplements, could introduce misclassification in exposure status, but it is likely to be nondifferential. The 69-item food frequency questionnaire might fail to capture all kinds of food consumed and underestimated total dietary intake. The time window of exposure is also critical in epidemiologic studies of diseases with long incubation period such as breast cancer. To improve accuracy and precision, we used two year from diagnosis as the point of measurement in the dietary survey. Another limitation is that we could not assess the dose of antioxidants from supplementation because doses of antioxidants from different producers, years and batches may be different. This might also affect accuracy and precision of our results. Antioxidants, either from dietary intake or from supplementation, may exert their effect over a long period of time. That may be the reason why we observed the effect for supplementation of 10 years or longer only. In addition, we could not adjust for the family history of breast cancer, benign breast disease, oral contraceptive use, hormone replacement therapy, and hormone receptor status in the analyses because the information was not available for all records. Furthermore, some of the risk estimates were based on small numbers of subjects, especially for some categories of supplementation; therefore, some of the significant associations may be due to due to chance.The recommended intakes  for adult women are 700 μg/day for vitamin A, 15 mg/day for vitamin E, 75 mg/day for vitamin C, 55 μg/day for selenium and 8 mg/day for zinc . CanadiaIn summary, our population-based study showed that supplementation of 10 years or longer of certain antioxidants such as beta-carotene, vitamin C, vitamin E and zinc may reduce the risk of breast cancer, although this study could not determine the overall effect of total dose or intake of antioxidants from both diet and supplement. Further investigations are warranted to confirm our results. The findings of our study may shed light on the prevention and control of breast cancer.The authors declare that they have no competing interests.The Canadian Cancer Registries Epidemiology Research Group contributed to data collection. SYP conceived the study, performed the analyses, wrote the manuscript and incorporated input from all other authors on the manuscript. JZ carried out part of the analyses and reviewed the literature. SWW provided guidance on data analysis and provided critical comments on the manuscript. LG, and HM directed the overall study and provided critical comments on the manuscript. All authors have read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/372/prepub


Communication of familial risk of breast cancer and melanoma has the potential to educate relatives about their risk, and may also motivate them to engage in prevention and early detection practices. With the Health Insurance Portability and Accountability Act (HIPAA) privacy laws, the patient often becomes the sole communicator of such risks to family members. This study surveys mothers diagnosed with either breast cancer or melanoma and their adult children about their family communication style, knowledge of increased risk, and early detection practices. In both cancer groups, most mothers alerted their children of the risk and need for early detection practices. Breast cancer mothers communicated risk and secondary prevention with early detection by breast self-examination and mammograms whereas the melanoma mothers communicated risk and primary prevention strategies like applying sunscreen and avoiding deliberate tanning. Open communication about health matters significantly increased the likelihood that children engaged in early detection and/or primary prevention behaviors. Examining the information conveyed to at-risk family members, and whether such information motivated them to engage in early detection/prevention behaviors, is key to guiding better cancer prevention communication between doctors and patients. Early detection of melanoma and breast cancer improves survival. For melanoma patients diagnosed early with Stage IA melanoma, the survival rate 10 years after diagnosis was estimated as higher than 95%; but this rate declines to less than 60% for later stage diagnoses , demonstrating the importance of secondary prevention such as skin self-examination (SSE) and visual inspection by a dermatologist . For brei.e., deliberate tanning). Secondary prevention practices include early detection steps such as breast or skin self-examination, mammograms, doctor visits, or genetic testing for BRCA1 and BRCA2 (breast) and CDNK2A  [Primary and secondary prevention practices are recommended for those at risk of developing the melanoma and breast cancer due to hereditary or behavioral reasons (elanoma) . PrimaryMothers, who serve as the nexus of communication of health information for the family, can enhance awareness of the risk of developing these cancers and provide social support for primary and secondary prevention behaviors ,7,8,9. WBoth breast cancer and melanoma disproportionately affect females. Furthermore, among all of the forms of cancer these are the only ones that empower the patient by providing a means for early detection by regular self-examination (breast and skin), thus, improving survival of the woman who chooses to engage in health promotion. Mothers, who are affected by the diseases, may play a pivotal role in enabling primary and secondary prevention practices among their children. If the child perceives themselves to be susceptible to the cancer, believes that the cancer has potentially serious consequences, believes engaging in early detection would be beneficial, and believes they can perform early detection practices, then the child is more likely to engage in such practices. The emotional impact of witnessing the mother’s sudden diagnosis with a potentially fatal disease may contribute to perception of risk . If a woThis study evaluates the communication between mothers who had either breast cancer or melanoma and their adult children to discover: if the mother believed having the cancer implied that her children have a heritable risk to develop the same type of cancer; the preventative measures the mothers suggested; and whether the adult children perceived the risk and followed the counsel of their mothers. During the summer of 2012, recruitment involved calling mothers from a list of eligible patients compiled by Enterprise Data Warehouse of Northwestern University Feinberg School of Medicine using the following eligibility criteria: female participants (mothers) between ages 38 and 75 who had a diagnosis of any stage of melanoma or breast cancer within the five years preceding the study. To be eligible, women also had to have at least one son and one daughter between ages 18 and 50. Criteria for exclusion were inability to speak and understand English, or did not have children. Adult children were eligible if they had a mother with a diagnosis of breast cancer or melanoma within the last five years and were between ages 18 and 50. Adult children were excluded if they were unable to speak and understand English. Mothers were called by telephone twice within a time period of two weeks. The mother voluntarily provided the contact information for her adult child or children. Attempts to contact one adult child were made three times at weekly intervals or until they were reached. If a mother was reached by telephone, reasons given for choosing not to participate were recorded as: no eligible children; no biological children; no English spoken; no melanoma/breast cancer diagnosis; privacy concerns; mother could not speak over the phone; mother not interested; mother thought child would not be interested. If the mother was interested in participating, the survey was completed by telephone. The adult child was subsequently contacted and could choose whether to participate or decline. If the adult child was interested in participating, then he or she completed the survey by telephone. For instances where the mother provided contact information for multiple children, the survey was given to the first interested child reached.Sequential and independent 10 min telephone interviews consisting of 29 items were conducted with the mother, followed by separate 10-minute telephone interviews consisting of 21 items with the adult child see . Verbal p < 0.05). Comparisons for each variable for the mother (p < 0.05). The engagement in early detection practices of children of mothers with breast cancer who reported open sharing of health information, was compared with those of mothers, who reportedly did not openly share health information (p = 0.05). Comparisons between breast cancer and melanoma mothers and children of these mothers were performed for each demographic variable.  (Fisher’e mother  and eache mother  (Fisher’ormation  (Fisher’p = 0.05).Similarly, sun protection of children of mothers with melanoma who reported open sharing of health information, were compared with the responses of mothers who reported their family was not open to sharing health information  . Additionally, 99 out of the 100 mothers and 97 out of the 100 children surveyed had health insurance  . MothersThe mothers in the breast cancer group often encouraged their children to engage in early detection measures, such as self-examination or a clinical breast exam by a physician. They also mentioned the use of hormones to their daughters as a potential risk. The mothers in the melanoma group focused on primary prevention, such as sun protection, and cessation of deliberate tanning. Mothers from both groups made the effort to increase their children’s awareness of risk, and also of healthy behaviors to engage in. Discussions of risk of cancer between mother and adult child occurred most often at the time of diagnosis with second conversations occurring after treatment. p = 0.0001).There was excellent agreement between the mother believing the child took the advice  and the child remembering the advice  (Cohen’s kappa = 0.97); however, the children did not act on the advice received from their mothers as often as the mothers believed. Less than half of the adult children in each cancer group acted on their mothers’ advice by seeing the doctor  . WhetherChildren of breast cancer mothers breast cancer were more likely to take early detection measures  than children of melanoma mothers  . Thirty-When the mother communicated cancer risk and possible actions, the adult children took action based upon their perception of their personal risk and their knowledge of appropriate behaviors by engaging in primary and secondary prevention practices. While mothers with breast cancer and those with melanoma equally told their children of their increased risk, the reasons for informing the child differed. Knowledge of family history and early detection measures, including genetic testing, were communicated by breast cancer mothers to their daughters more than by melanoma mothers. Mothers that had breast cancer focused on early detection measures, such as BSE or mammograms, while mothers that had melanoma focused on primary prevention measures, such as wearing sun block or ceasing deliberate tanning. The emphasis on primary prevention advice by mothers with melanoma may be due to the perception that melanoma is caused by environmental factors, unprotected exposure to ultraviolet light. Children that had open conversations regarding cancer risk with their mothers took significantly more action to detect cancer than children who did not have open conversations with their mothers regarding cancer risk. Many of these children performed early detection behaviors sooner than the recommended ages for screening the general population. In other areas of health behavior, the child’s perception of parental behavior is the strongest predictor of the child’s behavior, thus, the perception of open communication by the parent about their cancer experience serves to inform and enable the child’s behavior. Communication between mothers and their children in this study was an effective way of providing information relating to cancer risk and the appropriate primary and secondary preventative measures. Family members may serve as a hidden workforce supporting medical decision making and adherence to ongoing preventative health care . In thisPerceptions of familial risk are influenced by the physician informing mothers that the child may be at risk to develop the same type of cancer. While thirty percent of mothers with breast cancer recalled their doctor discussing the importance of the mother discussing it with their children, no mothers with melanoma recalled their doctor informing them of the potential for familial risk of melanoma. Communication of genetic risk, specifically discussing the option of genetic testing by the mothers in the breast cancer group may have activated adult children to perform early detection for breast cancer more often than was achieved by adult children of those with melanoma. This study identified the need for physicians providing care to mothers with melanoma to learn how to educate the mother about discussions with their children. Since first-degree relatives of melanoma patients with familial melanoma syndrome have a 10% incidence of developing melanoma, children of melanoma patients should be advised to perform SSE and to see a physician for a skin examination . The limited sample of women patients and their adult children were of higher socio-economic status than the general population, which limits generalizability. Nearly all of the adult children had health insurance, making their access to healthcare and preventative screenings perhaps easier than for those without insurance. Access to healthcare for the children of the mother communicating the risk of cancer and providing knowledge about prevention and the children’s engagement in early detection practices is influenced by health insurance. Family communication by the mother with her children can provide valuable knowledge and enhance the personal relevance of cancer prevention for the children at risk. Open communication between mothers and their children concerning health matters may be enabled by the physician encouraging the patient to discuss her cancer experience with the family. The physician may also suggest visiting trusted websites for additional information or provide written materials on early detection practices, involving both self-examination and doctor examinations. The recent emphasis on person- and family-centered care as a major initiative of the National Priorities Partnership of the National Quality Forum suggests an appreciation of family relevance in health reform and quality improvement . Physici


Associations between anthropometric indices of obesity and breast cancer risk may fail to capture the true relationship between excess body fat and risk. We used dual-energy-X-ray-absorptiometry- (DXA-) derived measures of body fat obtained in the Women's Health Initiative to examine the association between body fat and breast cancer risk; we compared these risk estimates with those for conventional anthropometric measurements. The study included 10,960 postmenopausal women aged 50–79 years at recruitment, with baseline DXA measurements and no history of breast cancer. During followup (median: 12.9 years), 503 incident breast cancer cases were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. All baseline DXA-derived body fat measures showed strong positive associations with breast cancer risk. The multivariable-adjusted HR for the uppermost quintile level (versus lowest) ranged from 1.53 (95% CI 1.14–2.07) for fat mass of the right leg to 2.05 (1.50–2.79) for fat mass of the trunk. Anthropometric indices (categorized by quintiles) of obesity , waist circumference , and waist : hip ratio ) were all strongly, positively associated with risk and did not differ from DXA-derived measures in prediction of risk.  Obesity imaging . AnthropUsing anthropometric approaches, and in particular BMI, many epidemiologic studies have shown that obesity is associated with increased risk of breast cancer in postmenopausal women –6. HowevGiven the limitations of anthropometric indices, studies that employ direct measures of body fat may yield more accurate estimates of the association between adiposity/obesity and breast cancer risk. DXA directly assesses bone mineral content and the soft tissue surrounding the bone by measuring the amounts of fat and lean tissue, and it can be used to both characterize body composition and provide precise estimates of fat, bone, and bone-free lean mass . Therefon = 68,132) or the Observational Study (OS) component  [The WHI is a large, multicenter study designed to foster understanding of the determinants of major chronic diseases in postmenopausal women. Women between the ages of 50 and 79 and representing major racial/ethnic groups were recruited from the general population at 40 clinical centers throughout the United States between 1993 and 1998 into either the Clinical Trial (CT) component  . The CT  93,676) , 13. WriSelf-administered questionnaires, completed at study entry, were used to collect information on demographics, medical, reproductive, and family history, and on dietary and lifestyle factors, including smoking history, alcohol consumption, and recreational physical activity . In addiin vivo cross-calibration was performed at two sites to convert QDR4500 to QDR2000-equivalent values [In the WHI, 11,393 women in three designated centers  had body fat measured by whole body DXA scans performed in fan-beam mode and obtained from Hologic QDR scanners  . Measurements were made at baseline and again at years one, three, six, and nine of followup. A standardized procedure for participant positioning and scan analysis was executed for all scans in the three centers. All DXA operators attended a central training session and were certified on the basis of an evaluation of scanning and analysis technique. Spine and whole body phantom scans were used to monitor scanner performance longitudinally . Qualityt values . These cClinical outcomes (including new cancer diagnoses) were updated semiannually in the CT and annually in the OS using in-person, mailed, or telephone questionnaires. Self-reports of breast cancer were verified by centralized review of medical records and pathology reports by trained physician adjudicators . As of MA total of 11,393 women had DXA measurements performed during the course of the study. Of these, we excluded 108 women (8 cases and 100 noncases) who were missing baseline DXA measurements and 325 women (26 cases and 299 noncases) with a previous history of breast cancer. This left 10,960 women available for analysis , of whom 380 (76.5%) cases and 7628 (72.9%) noncases were not in any intervention group , 6 (1.2%) cases and 289 (2.8%) noncases were in the estrogen-alone trial intervention group and not in any other, 19 (3.8%) cases and 314 (3.0%) noncases were in the estrogen plus progestin trial intervention group and not in any other, 50 (9.9%) cases and 943 (9.0%) noncases were in the dietary modification trial intervention group and not in any other, 26 (5.2%) cases and 644 (6.2%) noncases were in the calcium plus vitamin D supplementation trial intervention group and not in any other, 22 (4.4%) cases and 612 (5.9%) noncases were in the intervention groups of 2 trials, and 0 cases and 27 (0.3%) noncases were in the intervention groups of 3 trials. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations between various measures of body fat (see below) and risk of breast cancer. The outcome was time to breast cancer in days from enrollment. Cases contributed person-time to the study from their date of enrollment until the date of diagnosis of their breast cancer, and noncases contributed person-time from their date of enrollment and were censored as of the end of followup , the date of death, or the date of withdrawal from the study, whichever came first. 2), waist circumference (cm), and waist : hip ratio) were used as the exposure variables, and they were categorized by quintiles. In multivariate analyses, adjustment was made for established risk factors for breast cancer and for randomization assignment in the CT. Specifically, we adjusted for age (years) at baseline (continuous), family history of breast cancer , age (years) at menarche , age (years) at first full-term pregnancy , parity , age (years) at menopause , metabolic equivalents (METs) from physical activity , whole body percent fat, fat mass of trunk (g), fat mass of right leg (g), fat mass of left leg (g), and ratio of fat mass of trunk to average of fat mass of right and left legs ) and anthropometric indices of obesity (BMI (kg/mlsewhere ), histort was a function of measurements obtained only until the time of diagnosis in the index case. Among cases, measurements made within 1 year of diagnosis  were excluded from all analyses since these values may have been influenced by the presence of subclinical disease. In the second stage of the analysis, we analyzed the repeated body fat measurements and anthropometric indices as time-dependent covariates in Cox proportional hazards models to account for fluctuations in the measurements over time . With thc-indices  [c-indices from the different models we applied an ad hoc asymptotic z-test statistic assuming that the correlations between the c-indices are 0.5. The z scores were computed as (c1-c2)/sqrt(se2(c1) + se2(c2) − se(c1)*se(c2)), where c1 and c2 are estimated c-indices and se(c1) and se(c2) are their corresponding standard errors.Finally, in order to assess the predictive power of whole body fat mass and percent body fat versus BMI, of fat mass of the trunk versus waist circumference, and of the trunk : leg fat mass ratio versus waist : hip ratio, we computed l model)  by applyl model) . To testThe baseline DXA-derived body fat measurements and the anthropometric measurements were mostly moderately to strongly positively correlated with each other . HoweverDXA-derived whole body fat mass was positively associated with a history of diabetes, a relatively early menarche, intake of energy, and carbohydrate, and with Black race and (to a lesser extent) Hispanic ethnicity, and was inversely associated with ever use of hormone therapy (HT), and with alcohol intake and physical activity . For BMIAll baseline DXA-derived body fat measures showed strong positive associations with breast cancer risk . The mulData on estrogen receptor (ER) status were available for 437 cases . The DXA-derived body fat variables were all strongly positively associated with risk of ER+ breast cancer, but were not associated with risk of ER− breast cancer, and these estimates differed significantly from each other (data not shown). There were too few cases to allow meaningful analyses by combined ER/progesterone receptor status.quintile  5 versus quintile  1 = 2.55 (1.53–4.25) in never users and 1.37 (0.90–2.10) in ever users. However, on formal testing, there was no evidence of effect modification by HT use.When we stratified by ever use of HT, strong positive associations, of similar magnitude to those presented in in situ of the breast prior to the development of invasive breast cancer; and after excluding the first three years of followup  (data not shown). However, the results were somewhat attenuated after exclusion of the 83 cases and 1264 noncases who were very obese (BMI > 35 kg/m2) (accurate measurement of body composition is difficult in obese women [P = 0.12), and for fat mass of the right (P = 0.12) and left (P = 0.08) legs, were no longer statistically significant. The HRs (95% CIs) for the fifth versus the first quintile level were 1.47 (0.99–2.17) for whole body fat mass, 1.29 (0.89–1.87) for whole body percent fat, 1.69 (1.15–2.47) for trunk fat mass, 1.24 (0.86–1.78) for fat mass of the right leg, 1.40 (0.98–1.99) for fat mass of the left leg, and 1.75 (1.25–2.44) for the ratio of trunk fat mass : average of right and left leg fat mass.In sensitivity analyses, the patterns shown in se women , 22). Spp (trend) = 0.01, and those for BMI were 1.09 (0.79–1.49), 1.30 (0.95–1.78), 1.26 (0.91–1.75), and 1.73 (1.24–2.40), respectively, with p (trend) = 0.0003.All three anthropometric measures  were strongly, positively associated with breast cancer risk . The mulOf the 10,960 women who had baseline DXA measurements, 4,360 (40%) had measurements at year one (OS participants were not required to have DXA measurements at this time point), 8,906 (81%) at year three, 7,822 (71%) at year six, and 3,972 (36%) at year nine. Time-dependent covariate analyses of the anthropometric measures of obesity yielded strong, positive associations with breast cancer risk . Howeverc-indices for the DXA and anthropometric variables of interest were all very similar, ranging from 0.630 for BMI to 0.645 for waist circumference  or that for a model with WHR alone (c = 0.640). Similarly, fitting a model with WHR and total leg fat mass yielded a c-statistic of 0.649, which did not represent a significant improvement over those for WHR alone or total leg fat mass alone (0.636). Similar results were observed when we modeled WHR and fat mass of the right leg and WHR and fat mass of the left leg (data not shown).The mference . Further2). The results of the repeated measures analyses generally supported the findings from the analysis of the baseline measures. Finally, anthropometric indices of obesity were also strongly associated with increased breast cancer risk and they predicted risk as well as the DXA-derived measures of body fat.The results of the present study provide strong support for a positive association between body fat and breast cancer risk in postmenopausal women. The DXA-derived measures of body fat and fat distribution were associated with 1.5- to 2-fold increases in breast cancer risk (for the highest versus the lowest quintile level). The point estimates were strongest for fat mass of the trunk and for whole body fat mass, but the confidence intervals for these associations overlapped with those for all other body fat measures. There was no evidence of effect modification by ever use of HT, and the results were generally robust to various sensitivity analyses. However, the results were attenuated somewhat after exclusion of the very obese  and decreased adiponectin levels, as well as increased insulin/IGF signaling, elevated lipid levels, and, particularly in relation to breast cancer in postmenopausal women, an increase in aromatase expression in adipose tissue and a decrease in circulating sex hormone-binding globulin resulting (as mentioned earlier) in elevated bioavailable estradiol levels [There is now a substantial body of epidemiologic evidence supporting a positive association between obesity in postmenopausal women and breast cancer risk. In general terms, it has been suggested that the association of obesity with increased cancer risk may result from alterations in adipocyte biology or through alterations in the stromal-vascular fraction of adipose tissue . Hence, l levels , 47. Howl levels . in vivo cross-calibration.The present study has several strengths including its prospective design, long-term followup, large number of breast cancer cases, essentially complete ascertainment of cases and centralized pathology review, standardized protocols administered by trained staff for measurement of anthropometric variables and of body fat using DXA, repeated measures of the variables of interest over time, and the availability of information on a wide range of potential confounding factors. Limitations of the study include the fact that it was restricted to postmenopausal women, so that there were no DXA measures of body fat from earlier in life, and the limitations of DXA itself, including between-model variability in DXA measurements, although the latter issue was addressed by In conclusion, the results of the present study provide strong support for a positive association between DXA-derived measures of body fat  and breast cancer risk in postmenopausal women. They suggest further that anthropometric indices of obesity  predict breast cancer risk as well as DXA-derived measures of body fat.


Building on social science research examining the relationship between genetic knowledge, identity and the family this paper takes the cultural context of Cuba as a site for critical ethnographic engagement. The paper makes use of research working with a range of Cuban publics and genetic professionals as part of a collaborative research project exploring the social and cultural context of health beliefs about breast cancer. It illuminates the contrasting ways in which genomic knowledge linked to an increased risk of breast cancer is perceived, communicated, and acted upon. It is argued that the particular meaning and significance of genetic risk linked to breast cancer in this context must be examined in relation to long standing institutional practices relating to public health care provision. The focus on ‘the family’ in the provision of Cuban health provides a particularly viable foundation for the expansion of what is described as ‘community genetics’, including the collation of family history details for common complex diseases such as breast cancer. Nevertheless specific public perceptions of risk related to breast cancer and the difficulties of discussing a diagnosis of cancer openly in the family point to the very specific challenges for the translation and application of predictive interventions in Cuba. In summary the dynamic interrelationship between public health, perceptions of risk or health beliefs about the causes of the disease and attitudes towards cancer diagnosis within the family point to both continuities and discontinuities in the way that genomic interventions linked to breast cancer are unfolding as part of a dynamic yet still ostensibly socialist project of health care in Cuba. ► Intersections between genetic knowledge, the family and public health in Cuba. ► The meaning and significance of genetic risk linked to breast cancer. ► Community Genetics, family and the expansion of genetic medicine. ► Hereditary factors, gender and the significance of a ‘blow’ to the breast. ► ‘Continuities’ and ‘discontinuities’ between genetic medicine and public health. The multi-layered dynamics between genetic knowledge or technology and family relations are now being explored in a variety of ways across the social sciences. Early work examining how common sense ideas of heredity  and kinsPrevious research undertaken in the UK, suggests that the particular arena of medicine characterised as ‘breast cancer genetics’ offers an important context for examining the relationship between identity, genetic medicine and the family. Following the identification of the two inherited susceptibility genes BRCA1 and BRCA2 in the mid 1990s the growth and emergence of this new area of clinical practice has provided a rich context for examining the relationships between genetics and kin or family relations, both inside and outside the clinic. This has revealed the often contradictory consequences of genetic knowledge for collective and individual identity. On the one hand something of a productive fit between the field of medicine characterised as BRCA genetics and the family has been identified. This has been linked to gendered notions of female nurturance  or ideoloutside of Euro-American contexts are also now demonstrating how very different notions of personhood and meanings associated with kin, family, and/or citizenship have specific consequences for the meaning of and degree of engagement with genetic information. More broadly these studies point to the way differently situated moral values relating to spiritual, religious or community practices and institutional cultures, as well as state provision (or the lack) of health care may influence, facilitate or impede the application of novel biological knowledges and technologies  or general experience of breast cancer in the family or community. These responses have been analysed based on a grounded theory approach drawing on a thematic analysis of re-occurring topics  of genetic or what is understood as hereditary risk. This part of the paper reflects on the challenges to the practice of community genetics given both health beliefs relating to the causes of the disease and also the climate of fear and silence within the family associated with discussing a cancer diagnosis. The data presented in the second half of the paper suggests that despite the institutional culture that has long been focused on the health of the family, the meeting points between an expanding area of community genetics linked to identifying and acting on increased genetic risk of breast cancer, may not be so easily aligned and are in fact characterised by a range of discontinuities, tensions and differences.The development of a comprehensive public health system in Cuba emerged out of the success and commitments of the revolution in the late 1950’s. Since that time Cuban health care has long stood as an important symbol of the success of the Cuban socialist revolutionary efforts . This prMany commentators have suggested that understanding not just the symbolic significance of the ‘revolution’ in health care in Cuba over the last 50 years but also the logistics of its success, must be attributed to the system of so called ‘family medicine’ that began to emerge in the 1980s. The effort to provide more and better equipped family doctors who could attend to both the ‘physical and social well-being’ of the Cuban population was consolidated by the state in 1984 as part of the Family Physician and Nurse Programme (MEF) . This laThe emergence of ‘Community Genetics’ in the last six years, as part of a national programme of intervention, emerges directly out the ‘holistic’ and ‘preventative’ focus on family medicine and a long standing, nearly 40 year old programme of infant and maternal health. This is in part reflected in the way that many professionals now working in the field of community genetics previously worked as family doctors in their local communities, before retraining to become specialists in genetics. It is also reflected in the infrastructure for this new health focus and the way that it is being consolidated and linked to the system of primary care set up through programmes such as the MEF, with networks of genetic centres and clinics. Employing a total of more than 1600 persons, across the country, many regional centres have their own dedicated genetic specialists, technicians and nurses . Such ceThe main day to day focus of work in these centres is newborn neonatal screening to monitor for rare chromosomal conditions and in helping to facilitate the national programmes of pre-natal screening for conditions such as sickle cell anaemia. By comparison, the work of genetic teams in relation to complex adult onset conditions such as breast cancer is focused on the collection and collation of registries of families affected by such conditions. In some centres the list of conditions for which family history was being collected included, at the time of the research, schizophrenia, Alzheimers, heart disease, diabetes and more behavioural type conditions such ‘alcohol addiction’. With in total over 43,000 families forming part of a national registry, this is potentially a powerful resource for future genetic research and medicine . Yet dueMoving around rural and urban communities with different teams of medical geneticists in the three different provinces where the research for the project was undertaken it was clear that the genetic professionals were very much at the centre of their communities. Many had worked for years as family doctors living in or near the district in which they worked. Now as part of the program of Community Genetics, they could not walk down the street without encountering people they knew or more usually were stopped by people that recognized them. Frequent humorous comments were made by them about how their homes were like ‘consultorios’ every night, with neighbors, friends and acquaintances calling by to ask advice about health problems. On one occasion walking back to the community genetic clinic in the residential area of a small town in an eastern province, the doctor I was with was recognized and stopped by a mother and her teenage daughter. This was to discuss the fact that the daughter might be pregnant, and would therefore need an abortion. She had stopped the doctor to ask whom she should see at the local polyclinic about this. With a mixture of dismay and dry humour, about being so frequently stopped in the street and asked such queries, Celeste the doctor laughingly said that was community genetics in practice ‘es genetica communitaria en realidad!’. This social position at the heart of the communities where these health professionals lived was however particularly important in relation to the collation of family history details, as the experience of working with these health professionals illustrated.It is true to say that the social context of health beliefs and practices in relation to breast cancer, the main focus of our collaboration, was of some interest to these health professionals. They were attuned to consider these aspects of health and well-being, primarily as a result of prior involvement in a broad based system of family medicine orientated towards a ‘holistic’ preventative approach. Nevertheless this involvement was for them also explicitly about the task of recording and registering family history or identifying high risk families. It was not perhaps surprising therefore that they quite often literally took charge of these moments of completing the questionnaire, sometimes busily drawing up mini clinical family trees or firing further questions about dates or details relating to the history of cancer in the family. Yet unlike the sometimes tense atmosphere that such questions could generate in the clinical contexts in the UK, it soon became obvious that these were routine and expected questions for both practitioners and patients in Cuba. The ease with which such information was exchanged with medical practitioners, was particularly evident when, as was frequently the case, other family members became part of the discussions in the hunt for details of the history of disease. This was illustrated one afternoon walking around a residential housing area with two members of the local genetic clinic, after completing the questionnaire with an elderly woman in a nearby block of flats. On encountering the nephew of the elderly research participant, whom the geneticist also knew, he was asked if he knew about a particular cousin’s medical history, as his elderly aunt had been unable to remember. He was not surprised to be stopped in the street while cycling back home from work by the geneticist whom he also knew and responded with good humour and no hesitation to the request to clarify the details that his older relative had roughly sketched out.Asking and giving information about family history is part of the routine patient/practitioner dynamic in Cuba which the expanding field of ‘community genetics’ taps into and builds from. As the previous example demonstrates this was particularly evident in smaller communities where the relationship between genetic practitioners and the public was highly localised. Another illustration of this was the way genetic professionals would often become concerned that participants completing the questionnaires responded with what they perceived as the ‘correct answers’. Similarly when questions elicited blank or non-responses from participants, the geneticists would comment with open consternation, sometimes attempting to prompt participants and stating as one practitioner said, ‘ they do know the answers!’.Cuban geneticists, in their attention to the family, ante-natal and new born care are like other doctors powerful and embodied symbols of the revolution. The high profile programme of ‘Internationalism’ involving the export of thousands of doctors to Africa, Asia and South America for periods of one to three years has been central to this symbolic association of doctors with the revolution both within and outside Cuba . ImportaSpecial Period following the collapse of the Soviet subsidies in the late 1980’s and how this inspired her in her work. Since then she always wanted to be able to come back to the town where she had grown up and work. After doing her training in genetics she welcomed the opportunity to set up the community genetics service in her home town. Mayra’s dedication to the work is in fact noted by others who work in the centre - one nurse making some humorous yet nevertheless pointed remarks had earlier said in a semi ironic way how unlike the ‘other doctors’ who have left Cuba, Mayra is a ‘good communist’. Discussion with Mayra turns to talks of how she is going to put plants on the outside of the building to make the area more comfortable and welcoming for patients. She also mentions there is a sculpture that will be put up at the front of the building. She takes me to a small room where the sculpture which had been destined for this spot is currently being stored. It is a very classic representation of double stranded DNA. But she tells me that they aren’t going to use this one - she says it’s ‘feio’-ugly. The sculpture that will now be placed at the front of the building is something much more abstract and organic rather than obviously an object representing DNA or scientific knowledge. The choice of public sculpture at the entrance to the newly built community genetic initiative seems to symbolically reflect an effort to represent and position the work of medical genetics as part of the larger long standing project of community public health care. That is as a normalised aspect Cuban health care that directly builds on a long standing programme of public health, rather than something obviously novel or different.Mayra’s pride in showing me the newly built community genetics clinic, for which she is director, is evident. Unlike the generally old mainly very rundown buildings, the community genetics centre stands out as a gleaming newly painted building on a hill overlooking a provincial town in one of the eastern provinces of the country. Its location next to the maternity hospital in part symbolically reflects the way that Cuban Community Genetics builds on and extends the success of a widespread programme of maternal and infant health care. Inside the newly built centre the newness of the fixture and fittings is evident with work still going on to complete the centre. It is also one of the few buildings in the town with air conditioning. As we are walking around the as yet unused freshly painted conference room, which will be used for regional meetings of community genetic health professionals, conversation drifts into discussion of how Mayra got to be director of the regional genetics clinic here in this small town. She talks of being a family doctor in the Sierra Maestra in the difficult so called Long standing investment and organisation of public health in Cuba has in fact placed locally and community orientated family medicine at the heart of an endeavour, from which community genetics extends and builds from. This situation would also seem to provide a certain degree of leverage for the growth and expansion of genetic medicine in Cuba, including that linked to BRCA genetics. As the ethnographic material outlined above suggests family doctors and community genetic professionals are a vital component of this endeavour, situated at the heart of locally organised system of health delivery that is centred on the family. At the same time their commitment to integrating community genetics into the Cuban project of public health, while not always as uncritically supportive or unaware of the resource challenges to this endeavour in Cuba see , is noneAnalysis of aspects of the questionnaire data with Cuban women relating to open-ended questions concerning beliefs about the causes of breast cancer, risk factors for and the experience (if relevant) of the disease, points to the importance of a range of perceptions. In contrast to comparable research undertaken with clinical and non-clinical populations in the UK .‘Los genes son algo en la sangre que dan herencia y entonces para cancer tambien’Given the relative unavailability of predictive genetic testing in Cuba, an absence of hype and hope-filled discussion of the ‘BRCA’ genes in the media, as well as the virtual absence of a strong culture of breast cancer activism (certainly outside of Havana), it was perhaps not surprising to find that very few of the women completing the questionnaire had heard of the ‘BRCA’ genes. Rather more surprising perhaps was the fact that many had no point of reference to the term ‘genes’ or ‘genetic’ factors. There would often be looks of bemusement and doubtful shaking of heads in response to open questions asking if people had heard of ‘los genes’ or ‘la genetica’. For those few persons who for whom the term ‘genes’ was meaningful, discussion centred on a vague notion of something perhaps being transmitted in the blood. This was how a number of persons expressed this;It was significant that when similar questions about genetic risk were re-phrased in terms of ‘hereditary factors’ (‘factores hereditarios’) there was a much more widespread positive recognition. That is to say there was much more likely to be discussion and understanding that ‘la herencia’ (inheritance) and ‘la salud o las enfermedades’  of ‘los antecedentes’ or ‘antepasados’ (ancestors) might contribute to the risk of disease. This suggested that there was a particular cultural salience in this context surrounding hereditary risk, if not genes, genetic factors or more specifically the BRCA genes.same person. This was subtly illustrated in this respondent’s comments. Talking about where she had heard about the link between hereditary factors and breast cancer she said;‘en documentales por la television, en conversaciones con personas se habla de que es un factor importante porque hay varias personas en las familias affectadas. De como es que los genes producen cancer no lo he escuchado’This was particularly evident in the way that direct questions relating to genes, as opposed to hereditary risk factors, could elicit both strongly negative and positive responses often from the ‘pudiera ser una causa genetica, no ha escuchado en specifico sobre los genes en respecto de cancer de mama’.Another woman was more cautious in her response;Other persons were more definitive with some incredulous in response to the suggestion that breast cancer was linked to hereditary or genetic factors ‘la herencia no esta vinculado con cancer de mama’ (inheritance isn’t linked to breast cancer’). In another instance two sisters who had both in fact had breast cancer talked much about their shared experiences of living through the treatment ‘somos gemelos en respecto de cancer de mama’ said one of them (we are ‘twins’ when it comes to breast cancer). However they both refused and strongly refuted when prompted that there was anything hereditary in the fact that they had both had breast cancer.‘No tengo conocimiento de esto [factores geneticas]pero piensa que pueda ser hereditario o sea que uno nazca con eso y se manifeste a cualquier edad’(I don’t know anything about this[genetic factors] but I think that it could be hereditary or it’s that you are born with it and it can appear at any age’)One woman quite explicitly in response to a query about genes linked to breast cancer made a clear distinction between unknown genetic factors and known hereditary risk;While ‘BRCA genes’ and genetic factors more generally had little point of reference for many research participants, hereditary risk factors were, as these examples suggest, more readily associated with the increased incidence of the breast cancer. That is while some felt that factors such as having a family history might be important in the development of breast cancer specifically, there was nothing like the kind of reading of breast cancer as a ‘genetic’ disease that accompanied the high profile announcements that heralded the hyped and hope-filled discovery and application of new knowledge of the BRCA genes in the mid and late 1990’s in the UK and other Euro-American societies . It was This situation must in many ways be read in relation to the longstanding institutional culture and ideological values imparted through the Cuban project of public health care and the system of family medicine which has been in place in Cuba for the last 20 years. At the very least this ensures that attending to the history of disease in the family is commonplace. As one questionnaire respondent said in response to a query about why she believed hereditary factors were important in relation to breast cancer, ‘porque en las consultas siempre le pergunten si tienen antecedentes familiares con enfermedades’ . This was more succinctly and directly interpreted by one genetic professional who said ‘people are so used to questions about family history or thinking that it is important, because we are always asking them about it’.experience of breast cancer, reveals the extent to which biologized citizenship may be at stake in the Cuban arena  it was the former meaning that was most evident in the response of participants.‘piensa que los mas importante es el factor hereditario, porque no todos en su familia han tenido golpes’ . At other times this reasoning was inverted but in ways which still served to emphasise the importance of a ‘golpe’ in understanding the cause of breast cancer:For some it was a the fact that a physical blow might not be attended to in time which was perceived to be the problem. As one woman put it ‘los golpes que no se atendien bien pueden originar un coagulo y de ahi un cancer’ (the blows that aren’t looked after can develop a clot and then from there a cancer). This kind of statement reflected to some degree the importance of taking care of oneself, or ensuring that medical attention was sought. It also suggests that, at least for some, individual health awareness was not totally absent to this kind of reasoning.It is perhaps notable that particular ideas of female gender were sometimes caught up with discussion of the way a ‘blow’ to the breast was perceived as a risk factor for breast cancer. There was frequent mention that the breast was a ‘zona delicada para las mujeres’ – a delicate and sensitive area of the body for women which was susceptible to inury. More telling of was the way inappropriate activity for women or what was described as ‘fuerza fisica’ or ‘phyiscal force’ was also implicated in the development of cancer. In the opinion of some this could be linked to the novel need for women to undertake physical work as a result of economic demands following the ‘Special Period’ or it might refer to womens’ recent involvement in traditionally male sporting activities, such as boxing or weight building. Such perceptions would seem to reflect, in part, anxieties about the changing role of women in Cuban society. Highly illustrative of such feelings was a comment from one participant who believed it had been the blows she had received from a rifle during the pre-revolutionary struggle which she had participated in the late 1950s that had caused her cancer; ‘el mas importante creo que es un golpe, yo recibi golpes cuando la clandestindad me golpearon con la culata de un fusil’(I think the most important is a blow I received when a I was hit by rifle but by a secret campaigner).from without’  . Hunt poon the person, body or self, rather than being generated from within or which arise as a result of an individual’s own actions. Such readings seem to reflect a perception of cancer as not a product of ‘the body at war with itself’, as is common in western readings of cancer, . The absolute need for collective family engagement in predictive genetic medicine is perhaps most readily evident when the requirement to share information and pass on risk information breaks down in the family, impeding and sometimes preventing the pursuit of a genetic risk diagnosis for different members of the family . DespiteThis was illustrated on a number of occasions when working with Cuban health professional. On such occasions on arriving at the home of a potential research participant we would be met by an anxious relative of the chosen research participant. While they were often happy for the research questionnaire to be given to the person in question, they were concerned about their relative  being told that they currently had or had in the past been diagnosed with cancer or ‘el cangrejo’ – the crab, as sometimes the disease was metaphorically described. On some occasions this difficulty led to a decision to not undertake a questionnaire. In other moments when it was less clear if a relative had been told or not if they had or had had cancer open-ended questions were re-phrased by community genetic practitioners to avoid the use of the word ‘cancer’. In these situations, ‘problemas con las mamas’ (breast problems), ‘nodulos’ (breast lumps) and other euphemistic terminology would be used in circuitous ways by both practitioners, relatives and sometimes also research participants themselves in responding to questions. As recent studies in Cuba have suggested the tradition of non-disclosure of cancer diagnosis to the patient , reflectThis paper, drawing on fieldwork with a cohort of Cuban women and working with Cuban genetic health professionals has explored some of the uneven and disjunctured dynamics that characterise the translation of genetic medicine linked to breast cancer in a very specific national/cultural arena. It has been argued that the continuities and discontinuities that characterise this process must be situated in relation to a nexus of social practices and cultural discourses that both enable and challenge this endeavour in different ways. This includes the long standing institutional culture of Cuban public health care provision, research participants beliefs or perceptions about risk relating to breast cancer and the challenge of openly discussing a cancer diagnosis between patients or health practitioners in the context of the family.In one sense the Cuban case seems to point to the presence of particular continuities in the practice and provision of public health and novel interventions related to assessing genetic risk in common complex conditions such as breast cancer. Ethnographic evidence suggests that long standing locally organised aspects of the health care system, focused on family medicine, has helped to give meaning and significance to the idea of family history as a risk factor for disease whilst also furthered the emerging medical arena of community genetics. That is the work of collating family history and managing the delicate inter familial relations that are part of genetic interventions, are central to a tacit practice of care-giving within the community. Here doctors are situated as paternal guardians and gatekeepers of this and other health information. Although without technological or financial resources to undertake widespread predictive testing, being able to match genealogical data to clinical records confers a degree of scope and flexibility to an emerging and changing practice of Cuban medical genetics.outside or operate on the individual. This paper has drawn on illustrative examples relating to the perceived causative effect of physical blows to the breast and gendered ideas about excessive and what is understood as ‘unnatural’ physical activity undertaken by women. While further research and analysis of the large and diverse data set will further illuminate this finding, the data presented here highlights the need to examine the varieties of biosocial identities that are at stake in the translation of genomic technologies across a diverse national and transnational global terrain , ‘genetic risk’ has little meaningful resonance for many research participants. At the same time particular perceptions of risk are informed less by a discourse of individual moral responsibility than by an understanding of risk and danger that is more likely to be located in cancer causing agenets that exist  terrain . The finIn summary the very different configuration of factors that provide a context for the emergence of breast cancer genetics in Cuba provides a powerful illustration of the need for broader comparative perspectives in examining the relationship between genetic interventions and the family. The data presented here demonstrates the importance of examining the way that culturally and historically specific variables must be accounted for, as the work of translating predictive medicine is undertaken across comparatively different national arenas. This includes understanding the continuities, disjunctures and differences at stake in the dynamic relationship between genetic medicine, identity and the family.


Why does a first pregnancy after age 35 increase the risk of breast cancer, and what can be done to combat this? Related research article Haricharan S, Dong J, Hein S, Reddy JP, Du Z, Toneff M, Holloway K, Hilsenbeck SG, Huang S, Atkinson R, Woodward W, Jindal S, Borges VF, Gutierrez C, Zhang H, Schedin PJ, Osborne CK, Tweardy DJ, Li Y. 2013. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy. eLife2:e00996. doi: 10.7554/eLife.00996Image Pregnancy can accelerate the development of precancerous breast cells into cancerous lesionsBreast cancer is the leading cause of cancer deaths in women, killing more than 40,000 women in the US alone last year . It is aeLife, researchers at Baylor College of Medicine, the MD Anderson Cancer Center and the University of Colorado in Denver report that the answer to this question lies in a signalling pathway called the JAK-STAT5 pathway , the mated mice had more early lesions than age-matched unmated mice. However, the rate of cell proliferation was equal in both groups, which suggests that this phenomenon is not due to pregnancy causing precancerous cells in the mated mice to divide more frequently than in the control mice. Instead, the early lesions of the mated mice showed fewer signs of the programmed-cell death responses that would eliminate abnormal or precancerous cells that were seen in the unmated mice. Staining for cleaved caspase 3—a tell-tale sign of programmed cell death, or ‘apoptosis’—showed that pregnancy allows the precancerous breast tissue cells to escape processes that would normally cull abnormal cells. Haricharan, Dong et al. show that this occurs because precancerous cells in the pregnant mice activated the pro-survival machinery inside the cells to counteract the pro-cell death responses.The activated form of the protein STAT5, called pSTAT5—which has pro-survival activity—is detectable in most epithelial mammary cells, and its levels increase during pregnancy and lactation. The pregnancy hormones, placental lactogen and prolactin, are recognized by the receptor called PRLR, which causes the enzyme Jak2 to activate STAT5 and converting it to pSTAT5 . HarichaUsing AG490, an inhibitor of JAK-STAT signalling that blocks several tyrosine kinases including Jak2  as well The work of Haricharan, Dong et al. could lead to more effective strategies to both treat breast cancer and to reduce the incidence of breast cancer. Moving forward, validation of the present study and additional pre-clinical trials of STAT5 pathway inhibitors might pave the way for clinical trials in humans to reduce the risk of late-age pregnancy associated breast cancer risk.


The role of the familial cancer clinic (FCC) is to provide a cancer risk assessment and appropriate cancer risk management advice, but there are certain groups of patients for whom there are no standard risk management guidelines. One such group is women with a strong family history of breast cancer but BRCA genetic testing has not found a germline mutation. As a family history of breast cancer is the commonest reason for referral to FCCs, this clinical scenario is a frequent challenge to us all.This presentation will provide a summary of the literature surrounding:• Breast cancer risk in BRCAX families• Ovarian cancer risk in BRCAX families• Does the presence of male breast cancer affect the breast and ovarian cancer risks for women in BRCAX families