It is not known if the incidence of common cancers in Australian farm residents is different to rural non-farm or urban residents.Data from farm, rural non-farm and urban participants of the 45 and Up Study cohort in New South Wales, Australia, were linked with state cancer registry data for the years 2006–2009. Directly standardised rate ratios for cancer incidence were compared for all-cancer, prostate, breast, colorectal cancer, melanoma and non-Hodgkin Lymphoma (NHL). Proportional hazards regression was used to generate incidence hazard ratios for each cancer type adjusted for relevant confounders.Farm women had a significantly lower all-cancer hazard ratio than rural non-farm women . However, the lower all-cancer risk observed in farm men, was not significant when compared to rural non-farm and urban counterparts. The all-cancer adjusted hazard ratio for combined rural non-farm and urban groups compared to farm referents, was significant for men  and women . Confidence intervals did not exclude unity for differences in risk for prostate, breast, colorectal or lung cancers, NHL or melanoma. Whilst non-significant, farm residents had considerably lower risk of lung cancer than other residents after controlling for smoking and other factors.All-cancer risk was significantly lower in farm residents compared to combined rural non-farm and urban groups. Farm women had a significantly lower all-cancer adjusted hazard ratio than rural non-farm women. These differences appeared to be mainly due to lower lung cancer incidence in farm residents. Registration of all cancers, excluding non-melanoma skin cancers, is a legal requirement in all Australian States , 2. The International studies have reported mixed findings on comparative cancer incidence between farmer and non-farmer groups. Most recent studies have reported reduced cancer incidence in farmers for all-cancer lung, breast and colorectal cancers –13, PossThe current study aims to examine whether associations between cancer incidence and being a farmer or farm resident noted in other studies, are apparent in a large Australian cohort. From a rural health perspective, it also aims to differentiate the incidence of common cancers between farm residents and other rural people, not often specified in other studies. Findings may assist rural health programs better target cancer prevention intiatives; and/or highlight risk factors and exposures that require further investigation.This data linkage study was based on the 45 and Up Study cohort, consisting of 267,119 residents of New South Wales (NSW), Australia, aged 45 years and over. The cohort database is maintained and managed by the Sax Institute, in collaboration with health agency partners.45 and Up Study website [Between January 2006 and December 2009, eligible NSW individuals 45 years and over, were randomly sampled from the Australian Department of Human Services database which provides near complete coverage of the NSW population. Persons aged 80 years and over and residents of rural and remote areas were oversampled by a ratio of 2:1. A pilot study was undertaken to validate recruitment procedures and refine survey questions. Subjects were mailed a questionnaire with a consent form for follow-up and data linkage to routine health databases. An additional 0.5% of the final cohort comprised volunteers who contacted the Study hotline to participate. The overall response rate for sampled individuals was 17–18%; representing approximately 11% of the NSW population aged 45 years and over . The bas website .Participant records from the 45 and Up Study cohort provided information on residence , age, family history of cancer, household income, screening practices, diet, obesity, sun exposure, smoking and alcohol consumption. Cancer incident cases amongst participants were identified through linkage to the NSW Cancer Registry data, which contains records of all cases of cancer diagnosed in NSW residents, excluding non-melanoma skin cancers. Records were available for all new cancer notifications for the period 1st February 2006 (2006 was the first year in which 45 and Up Study participants were recruited) to 31st December 2009. Cancer type is derived and coded according to International Statistical Classification of Diseases Ninth Edition (ICD-9) cancer groupings .Data linkage was conducted by the NSW Centre for Health Record Linkage, using a probabilistic record linkage method. Detailed information on data linkage methods is available elsewhere , 34. Fig‘Farm residents’ were defined as those who indicated that they lived in a ‘house on farm’ in the 45 and Up Study baseline questionnaire. Rural ‘non-farm’ and urban residents were further defined using the Accessibility/Remoteness Index of Australia (ARIA+) from postcode of residence at recruitment . Those pCharacteristics of the cohort in relation to risk factors of interest included age and others categorised in accordance with current national health or workplace recommendations –43. ThesAnalyses were conducted using SAS 9.3™ . softwar45 and Up Study Collaboration recommendations, only internal comparisons between sub-groups within the cohort were made [45 and Up Study. Age-specific rates from each sub-group were used to derive an expected rate in the reference or standard population. This expected rate was divided by the standard population incidence rate and multiplied by 100 to derive a standardised rate ratio. Variance of observed counts were based on the Normal approximation or the Poisson distribution where less than 30 events occurred within a resident group [Consistent with ere made . Direct ere made . The refnt group . Directlp values < .25 were included in the base model. Interaction terms between variables in the base model and cohort were created and tested for effect modification. Models were progressively tested using backward elimination methods to the .05 level of significance; with non-significant variables also checked for confounding effects on the hazard ratios of cohort groups. Residual plots were examined to ensure assumptions of proportional hazards regression were met.Cox proportional hazards regression was used to model potential differences in incidence of selected cancers by cohort, controlling for risk factors . VariablSensitivity analyses were conducted using a smaller subset of data, where participants with prior cancer were removed and time to event for all records was limited to time since completing the questionnaire. However, results are primarily presented for the larger dataset, with reference to the comparison dataset as appropriate.61.2 years (95%CI 61.0–61.4), compared to 63.7 years for rural non-farm (95%CI 63.6–63.8) and 64.3 years for urban counterparts (95%CI 64.2–64.4). Similarly, the average age of farm women was 58.6 years (95%CI 58.5–58.8); younger than rural non-farm at 61.8 yrs. (95%CI 61.7–61.8) and 62.5 years for urban women (95%CI 62.4–62.5). Other summary characteristics of the cohort are available elsewhere [Information from the 45 and Up Study survey questionnaire was available for 267,119 participants. Forty five records were removed for which dates of recruitment, age or gender information across datasets was incomplete or inconsistent. The remaining 267,074 participants were followed for 1,006,229 person-years . Standardised rate ratios for cancer incidence and adjusted hazard ratios by gender for each cancer are shown in Tables lsewhere .Table 2CAll-cancer incidence rate ratios and the adjusted hazard of cancer diagnosis in farm men was almost 10% lower than in rural non-farm and urban men, although not significant between subgroups. However, when rural non-farm and urban men are combined as a group, the hazard ratio was 1.08 (1.01–1.17) compared to farm men. Farm men also had the lowest lung cancer and highest melanoma incidence, but these were not significantly different to either the rural non-farm or urban groups. There was little difference between farm men and other groups for NHL, prostate or colorectal cancer.All-cancer incidence was lowest in farm women with the rate ratio 12–14% lower than either of the other groups, although differences were not significant. When controlling for other factors, the all-cancer adjusted hazard ratio for farm women was also 12–14% lower than other groups; being significantly lower than rural non-farm, but not urban women.. Similar to men, the hazard ratio relative to a combined rural non-farm and urban group was 1.13 (1.04–1.23), which was also significantly higher than that of farm women. There were no significant differences in rate ratios or adjusted hazard ratios between residence groups for any of the individual cancers tested. However, whilst confidence intervals did not exclude unity, both the incidence and adjusted hazard of lung cancer in farm women were around half that of other women. Results for the sensitivity analyses, which captured approximately 38% of cases across the selected cancers, were generally consistent with findings for the main analyses for both men and women and are reported elsewhere .Farm residents in this cohort were younger than rural non-farm and urban residents, with age controlled for in all adjusted hazard models. Family history was associated with most of the selected cancers, although this information was not available for NHL. Smoking status was significantly associated with lung cancer, with the adjusted hazard ratio for current smoking 18 times that of never smokers in men; and 9 times that of never smokers amongst women. In contrast, current smoking was negatively associated with prostate cancer and melanoma in men; as was income for lung and all-cancer in men. Tannability was negatively associated with melanoma in both genders. For women, higher sun exposure appeared weakly protective against breast cancer, but increased risk for melanoma. Overweight and obesity were associated with greater likelihood of both all-cancer and breast cancer in women. Income and red meat consumption were non-significant confounders for some cancers; whilst alcohol consumption was not associated with any of the cancers of interest.Rate ratios for cancer incidence and adjusted hazard ratios are both discussed, although it is recommended more weight be given to the latter, as they control for additional risk factors. All-cancer incidence and adjusted hazard of a cancer diagnosis was lower in farm men, but differences were not statistically significant when compared to rural non-farm or to urban men separately. Farm women had non-significantly lower all-cancer incidence; but the adjusted hazard of a cancer diagnosis in farm women was significantly lower than rural non-farm women, controlling for other factors. There were no significant differences in either the standardised rate ratio or adjusted hazard ratio between cohorts for any of the individual cancers tested; although the incidence and adjusted hazard of lung cancer in farm women was around half that of other women. In this study, smoking was the most prominent modifiable risk factor in adjusted hazard models, having a particularly strong association with lung cancer. However, men who were current smokers were half as likely to be diagnosed with melanoma; and women with higher weekday sun exposure were least likely to be diagnosed with breast cancer.Consistent with the direction of the findings, most reviews and recent studies have reported reduced all-cancer incidence in farmers , 52, 53.Comparative measures of smoking, alcohol and income-related risk factors for resident groups in this cohort presented elsewhere were generally more favourable amongst urban residents . HoweverDespite the small number of farm resident cases in this study for men and women, the lower lung cancer incidence and risk in farm residents support data from other studies reporting on farmers –13. LoweThere was little discernible difference between groups in our study for the other selected cancers. Most recent studies of colorectal cancer in farmers have reported reduced incidence or risk in farmers. These have predominantly been large occupational cohort studies with a minimum follow-up of ten years –13. FourFindings for breast, melanoma and prostate cancer in farmers have been mixed, with several reporting no significant differences between farm and non-farm groups , 63–66. One prominent meta-analysis highlighted the inconsistencies of results brought about by variations in study design, risk measures, farmer definitions and geographic location . A positOther studies have suggested increased cancer incidence in rural areas may be attributed to higher smoking and alcohol use, lower access to or utilisation of health services; and employment or income disadvantage , 75. A gNevertheless, findings support what is already known about the hazardous effect of smoking upon lung cancer and all-cancer. It also supports the current health promotion priorities of Australia’s health systems with a focus on prevention and reduction of tobacco use, especially amongst groups with a higher prevalence of smoking . The negA related study of cancer mortality risk in this cohort, found that compared to very low exposure, weekday sun exposure of 1–4 h was protective against NHL, prostate, breast, melanoma and lung cancer mortality . This waSeveral studies have explored positive associations between cancer incidence and farm environmental exposures, such as pesticides. However, these are outside the scope of this study, as they do not generally compare farm and non-farm groups; and farm exposure information was not available in this dataset.The negative significant association between lung cancer in men and income, is consistent with findings elsewhere, relating to higher levels of smoking in lower socio-economic groups . OverweiThere are a number of limitations in this study that may have affected the results. Firstly, data on incident cases at the time the research was conducted were only available for a relatively short period of follow-up, resulting in low power and wide confidence intervals for some analyses. This may have impacted upon the significance of some findings, favouring a bias toward the null. Discussion of results with confidence intervals that include unity should be considered exploratory; and larger, consistent differences given more weight. Nevertheless, results still offer insight into potential differences and guidance for further work.In addition, to maximize both cases numbers and follow-up time, this study included all records of cancer for participants who could potentially receive a diagnosis of cancer at any time in the 2006–2009 study period; that is, cancer diagnosis in some participants could have preceded their enrolment in the 45 and Up Study. However, such an effect is likely to be non-differential relating to residence; and results of the sensitivity analyses were consistent with and support the main findings.The need to exclude records with missing variable information from models may have impacted upon the results, although this is not likely to have been differential across groups or between cases and non-cases. Other limitations include the potential mobility of participants regarding their residential status and that only the more commonly known risk factors were considered for analyses. A myriad of other potential risk factors and confounders were not measured ; and may have contributed to the differences observed.The 45 and Up Study, even with its robust sampling methods, is not necessarily representative of the population of NSW aged 45 and over . HoweverThe definition of a ‘farm resident’ in this study was also open to respondents’ interpretation of ‘farm’, which could include small holdings used for commercial, recreational or both purposes. Exposures could be quite different depending on which of these purposes was dominant. Farm exposure differences and errors arising from misclassification of residence, are likely to have lessened any differences between resident groups, but not likely to have systematically affected non-residential risk factors. Therefore, any potential bias is likely toward the null and an underestimation of a relationship between farm residence and cancer incidence.This study is the first to examine differences in incidence of cancer between farm, rural non-farm and urban residents in Australia. Controlling for a range of risk factors, farm women had a significantly lower hazard ratio for cancer diagnosis than rural non-farm women. Farm men also had lower risk of cancer diagnosis, but this was not statistically significant compared to rural non-farm and urban men. When combining rural non-farm and urban groups, the all-cancer adjusted hazard ratio was significantly lower in both farm men and women, due to increased precision.Differences between groups in the risk of prostate, breast, colorectal or lung cancers, NHL and melanoma were not significant after controlling for commonly known risk factors. However, notwithstanding small case numbers and a lack of statistical significance, farm women had around half the risk of other women in being diagnosed with lung cancer; controlling for smoking and other factors. Differences in all cancer risk appeared to be mainly due to lower lung cancer incidence in farm residents.


Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome – related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care. Metabolic syndrome (MetS) is increasing in incidence and lead to significance cardiovascular disease (CVD) and mortality. CVD includes all the disease of the heart and circulation including coronary heart disease, angina, heart attach and stroke. MetS can also raise the risk of other diseases, including cancer. It's thought that more than 2 in 10 cancers in the UK are linked to being MetS. The relationship between MetS and cancer is complex. Individual components of the metabolic syndrome are known as risk factors for incident cancer disease, but it is not clear how the clustering of these components is linked to the development and progression of tumors. It seems self-evident that a condition characterized by multiple risk factors, as the metabolic syndrome, will carry a greater risk for adverse clinical outcomes than will a single risk factor. Therefore, a better understanding of the relationship between components of the metabolic syndrome and whether and how these components contribute to progression of cancer and its incidence could inform more effective prevention strategies [MetS rises with economic development, sedentary lifestyle and associated overweight and obesity as seen among populations in Asia, South and North America, and Eastern Europe. As a result, the metabolic syndrome is now both a public health and a clinical problem. MetS has existed in various forms and definitions ; howeverThe third National Health and Nutrition Examination Survey (NHANES III) criteria have shown that about 47 million people have MetS , 6. The Interestingly patients with MetS are at twice the risk of developing CVD over the next 5 to 10 years as individuals without the syndrome, whereas it has been shown that metabolic syndrome confers a 5-fold increase in risk for type 2 diabetes . On the et. al analyzed 38,940 patients affected by cancer and MetS through a meta-analysis and it has been shown that the MetS is associated with an increased risk of several cancers including colorectal, pancreas and liver cancers. However, many of the reported associations might differ between sexes. In men, MetS was strongly associated with liver  and colorectal  cancers and weakly associated with bladder cancer . While in women, the presence of metabolic syndrome was associated with endometrial , pancreas , breast , colorectal  and ovary cancers  [Recently, Esposito The increasing prevalence of MetS worldwide and the high incidence of some malignancies, imply that every year many cases of cancer are attributable to metabolic syndrome. Primary prevention and early detection of cancer are recommended for patients affected by fully developed diseases.It's important to underline how interventions to reduce the prevalence of metabolic syndrome in adult populations will reduce cancer risk  thereforet al. have conducted a study to examine the association between MetS and all-cause cancer mortality, in which participants were only men enrolled in Aerobics Center Longitudinal study (ACLS)  who, at the time of examination, were free of known cancer. Using criteria of the NCEP-ATP III, men have been divided into two groups according to have or not MetS. The study has shown that men with MetS had a 56% higher risk of cancer mortality compared with those with only one condition. Moreover, participants with 3 or more risk factors had an 83% higher risk of cancer death compared to men without risk factors. With the exception of high blood pressure, the only component that did not increase cancer risk, it has been shown a positive association between cancer mortality and each of the MetS components. The presence of MetS was then significantly associated with increased risk of cancer mortality for lung and colorectal cancer.Jaggers et al. reported through prospective cohort study that woman affected by breast cancer and MetS are non-responders to standard treatment than those without MetS. So preventing or controlling the risk factors of MetS would be one of the possible ways to reduce cancer deaths in both sexes [Features studies must be done to analyze the connection between MetS and all cause cancer mortality among female population, although previous studies have shown lower risk of cancer mortality for woman with MetS . Recentlth sexes .MetS can also represent a common long-term complication after cancer treatment that affects life expectancy and quality of life. For example, in childhood sarcoma survivors who received chemotherapy, the prevalence of the metabolic syndrome was 33% compared with data in healthy population ; for aduPatients affected by MetS present several biological and physiological alterations which may increase risk of neoplastic transformation or increase progression of existing cancer.We desire to summarize the main aspects that link MetS and risk of cancer Figure .2) and 312 million are obese (BMI ≥30 kg/m2) [The high rates of obesity are a worldwide problem: the International Obesity Taskforce estimates that 1.1 billion people are overweight  .There are two categories of adipose tissue: brown adipose tissue (BAT) and white adipose tissue (WAT), the last one is also divided in subcutaneous and visceral. The visceral-adiposity stores energy as triglycerides and protects organs from mechanical stress. Several epidemiological studies confirmed the relationship between visceral adiposity and an increased risk of developing certain types of cancer –19 incluWAT is an active endocrine organ secreting local and systemic hormones (such as leptin and adiponectin), cytokines (such as TNF-α and iterleukin-6) interacting with the immune system and various growth factors: insulin-like growth factor (IGF-1), insulin-like growth factor-binding protein (IGFBPs) and transforming growth factor (TGF-β) .Adipokines  are synthesized by adipocytes and regulate many physiological processes, in particular, appetite, angiogenesis, metabolism of glucose and fatty acids, as well as inflammatory and immune reactions .Adiponectin is the most abundant hormone in circulation (0.05% of serum proteins) secreted after activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) in fat cells. It enhances metabolism of glucose and fatty acids (reduction of FFA concentration) in liver and muscle and increasing insulin sensitivity , 25. AdiA low level of adiponectin is due to adipose tissue hypoxia and this is correlated to a higher risk to develop breast, endometrial and gastric cancers .Leptin is known as the hormone that reduces food intake giving a feeling of satiety , 29 as iAdipocytes, in addiction, secretes proangiogenic factors; among them Vascular Endothelial Growth Factor (VEGF), is one of the most important. VEGF is stimulated by hypoxia and implicated in angiogenesis, fundamental for tumor formation and metastasis . One recWAT could be a source of mobilizable progenitor cells : adiposeSeveral studies have shown a higher mobilization and recruitment of ASCs in obese patients that lead to stimulation of tumor growth, promotion of angiogenesis and increasing of cancer cells invasion. The great number of circulating ASCs, differentiates in perivascular cells that provide oxygen and nutrient to tumor, inducing an augment survival and limit apoptosis of cancer cells.et al. have analyzed the role of ASCs in breast recurrence, after surgery, in patients who undergoing autologous fat graft for breast reconstruction and have shown that ASCs are tumorigenic in presence of breast cancer cells which express the tyrosine-kinase receptor c-Met. Moreover the co-injection of ASCs and breast cancer cells in nude mice produces a tumor more vascularizated and increased in size [Vincenzo Eterno  in size .Insulin is the most potent anabolic hormone, secreted by the pancreatic β-cells located in the islets of Langherans. It has a significant role in glucose, fat and protein metabolism . InsulinIn healthy individuals, blood glucose concentrations are maintained through a state of balance between insulin production and insulin-mediated glucose uptake in target tissues  determinMetabolic syndrome is also characterized by increased circulating glucose (hyperglycemia). Glucose excess can be converted to macromolecular precursors such as acetyl-CoA for fatty acids, glycolytic intermediates for nonessential amino acids, and ribose for nucleotides . ConsideFurthermore certain types of cancer have been associated with some Tricarboxylic Acid Cycle (TCA) enzymes mutations, including isocitrate dehydrogenase (IDH1 and IDH2) , succinaMalignant tumor growth is supported also by altered activity of several glycolytic enzymes such as the overexpression of hexokinase  and 6-phet al. in a prospective study [Several studies of patients with different tumor types have confirmed that increased glucose uptake/accumulation by tumors, correlates with a higher grade of tumor, incremented metastatic potential, reduced response to therapy and poorer survival. Data showed a statistically significant increase in risk of pancreas cancer, malignant melanoma, and urinary tract cancers among subjects who had elevated levels of fasting glucose. The relationship of hyperglycemia with the risk of cancer overall and of cancer at organ specific sites was emphasized by Stattin ve study .Recently our group showed that the hyperglycemic state is sufficient to accelerate lung cancer development in an oncogene K-Ras mouse model.in vivo, grew faster than euglycemic hosts and showed a more malignant growth behavior. Moreover, our current study provides compelling evidence that hyperglycemia, after activation of oncogenic K-Ras, exerts its pro-tumorigenic effects by maintaining a sub-population of cancer tumor-initiating cells, namely lung bronchio-alveolar stem cells (BASCs) [Indeed, K-Ras-driven tumors exposed to hyperglycemia  (BASCs) .Various signaling pathways that cooperate to control cancer cell behavior are activated by high glucose. Indeed several studies suggest that high glucose induces cancer cell invasiveness and migration through stimulation of epithelial-mesenchymal transition (EMT), a complex process critical for the acquisition of migration, invasiveness and pluripotent stem cell-like phenotype .et al. [Recently, Dong et al.  suggesteet al. .So these data further support the hypothesis that tumor-promoting activity of hyperglycemia can be associated with several aspects of oncogenesis.The IGF system is a complex molecular network that includes two ligands (IGF-I and IGF-II), two receptors (IGF-IR and IGF-IIR), six high-affinity-binding proteins (IGFBP-I-IGFBP-VI) and several binding-protein proteases , 61. IGFIGF-I binding to IGF-IR activates two main signaling pathways: phosphatidyloinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway. Stimulation of PI3K pathway leads to activation of several downstream substrates, including PKB. Its active form (Akt/PKB) enhances proliferation, tumorigenesis and self-renewal by activating mammalian target of rapamycin (mTOR) and forkhead box O (FoxO), and blocking glycogen synthase kinase 3β (GSK3β) that result in accumulation of β-Catenin and in activation of its downstream targets .The same effects are also achieved through the activation of Ras/MAPK/extracellular signal-related kinase 1/2 (ERK-1/2) (21).Cancer cells show significant overexpression of IGF-I and its receptor. High circulating levels of IGF-I, are associated with increased risk for several cancers, including breast , prostatThe involvement of IGF-I in cancer progression is supported by several clinical and experimental studies. A significantly increased risk for prostate cancer development is due to an augment of circulating IGF-I as shown by Price et al. (2012) , others In vitro studies on human colon cancer cells showed cells proliferation promotion by IGF-I, an overexpression of IGF-IR, and inhibition of tumor cell growth using its monoclonal antibody ; moreoveIn familial breast cancer an association between high IGF-I levels and cancer development has been proved –75 and iRegarded cancer metastasis recently has been documented a role for the IGF system in several human cancer such as colorectal  and gastIGF-IR is also expressed by endothelial progenitor cells from bone marrow (EPCs). BM-derived cells are precursors for both hematopoietic and endothelial cells; in particular EPCs represent the non-hematopoietic (CD45-) BM derived cell population .Exciting new data have shown that tumor neovascularization, which supports growth and dissemination of tumors, involves recruitment of EPCs. An increased mobilization of EPCs has been associated with cancer, vascular injury, and poor prognosis in patients with lymphoma, thus establishing the significance of these cells in tumor progression.BM-derived cells are thought to merge with the wall of a growing blood vessel, where they differentiate into endothelial cells . After tRecently some insights have been obtained about the role of IGF in progenitor cells relocalization, suggesting a role of IGFs during BM-derived cell mobilization.IGF has an important role in the angiogenic processes, indeed tumor neovasculature is also influenced by IGF which promoting proliferation and migration of endothelial cells, mobilization and colonization of tumor niche by BM-derived cells.MetS is frequently associated with inflammation. Regarding hyperglycemia is well-known that an excess of glucose promotes formation and accumulation of advanced glycation end-products (AGEs) . AGEs biEven inflamed adipose tissue may play a critical role in pathogenesis of several cancers, such as breast, colon, pancreas, and kidney .Visceral adipose tissue can release several cytokines as tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) which are considered to form a link between inflammation and cancer. Indeed it has been shown, in obese women, elevated circulating levels of TNF-α and IL-6 which are associated with development and progression of breast tumors . These cParticularly TNF-α activates two pathways: MAPK and NF-kB pathway. NF-kB is a transcription factor that activates the expression of genes which promote cell proliferation, inhibit apoptosis and therefore enhance cell survival. NF-kB also increases production of nitrogen oxide (NO) and favors formation of ROS .Another family of small cytokines is chemokines, of which the circulating Monocyte Chemoattractant Protein-1 (MCP-1) promotes the recruitment of monocytes to adipose tissue, where the cells differentiate and become macrophages .Infiltrated macrophages surround the adipocyte in a histologically characteristic pattern known as crown-like structures (CLS)  and effeMoreover, components of metabolic syndrome have a positive correlation with C reactive-protein (CRP), an acute phase protein synthesized and secreted by the liver .Particularly it has been shown a highly significant correlation between visceral adiposity and CRP, and also patients with increasing number of metabolic syndrome components presented a linear increase in CRP levels . This prHence CRP can probably be used as a marker of chronic inflammation in metabolic syndrome patients.Visceral adiposity regulates the synthesis of the endogenous sex steroids such as estrogens, androgens and progesterone through several mechanisms. In particular in men and postmenopausal women, adipose tissue is the principal site of estrogens synthesis .In fertile women estrogens, of which oestradiol is the major, are predominantly produced by the ovary. Whereas in menopause, estrogens production decreases and remains a peripheral conversion, primarily in the adipose tissue, of androgens by the cytochrome P450 enzyme aromatase located in adipocytes . As a reAnother consequence of increased visceral adiposity is reduction in hepatic synthesis and blood concentrations of sex-hormone binding globulin (SHBG), a plasmatic binding protein with high specific affinity for estradiol  that genEpidemiological studies have given several evidence that this shift in circulating levels of sex steroids, induced through adiposity, could in large part explain the associations between anthropometric indices of excess weight and risks of breast  and endometrial  cancers. Especially estrogens show a central role in regulating cellular differentiation, proliferation and apoptosis induction –94 in thIndeed in estrogen receptor-positive breast and endometrial cancers, estradiol acts as a powerful growth factor that supports tumor growth; estrogen activity through different and complex mechanisms may promote tumor development and progression.via ER-α agonism as well as induction of vascular endothelial growth factor and angiogenesis [via genotoxic metabolites [Direct effects of estrogens include stimulation of cellular proliferation and inhibition of apoptosis ogenesis , 96. Furabolites .Differential effects of menopause on cancer incidence observed in epidemiologic studies point to the potential role of estrogen in development and progression of these malignancies.In postmenopausal women risk of estrogen receptors-positive breast cancer development is inversely related to blood levels of SHBG , 98, repMany therapeutic approaches are studied to face the metabolic syndromes and its impact on development and progression of certain types of cancer.As described above, insulin is the most important hormone in the metabolic syndrome and its binding with receptors induces inhibition of apoptosis and promotes cell proliferation. Cancer cells are characterized by an overexpression of insulin receptors (IGF-R) suggesting their important role in tumorigenesis and growth. In addition, surrounding stromal tissue of tumor cells produces IGF-I and IGF-II  suggestiAnother condition of metabolic syndrome associated with multiple cancers is obesity. This metabolic condition is characterized by the deregulation of adipokines such as leptin and adiponectin responsible of maintenance of metabolic homeostasis and inflammation, angiogenesis, proliferation and apoptosis modulation.For therapeutic approach an important aspect should be to consider that adiponectin can antagonize the actions of leptin. If adiponectin has been shown to decrease growth and proliferation, increase apoptosis, decrease invasion and vessel density in murine cancer models, leptin has been shown to increase proliferation, migration, and invasion of cancer cells.in vivo [in vitro cells reduced the proliferation in a dose-dependent manner [Elevated leptin levels have been reported in hepatocellular carcinoma and prostate cancers whereas levels are unchanged in breast cancer patients where leptin receptor expression is instead enhanced. At the same time, adiponectin single-nucleotide polymorphisms have been shown to increase prostate, colon and breast cancer risk. As therapeutic approach recent evidence suggests that soluble leptin receptor can act to bind circulating leptin attenuating its activity, although additional preclinical studies are needed to test the real efficacy in vivo . Moreovet manner . Alternavia an LKB1-dependent mechanism; liver kinase B1 (LKB1) is a protein threonine kinase that has tumor-suppressor activity and it is frequently loss in human cancers  which induces insulin-sensitizing. TZDs which are PPAR-γ agonists increase the secretion of adiponectin from adipocytes altering tumor development but after a long-term treatment. If glitazones (PPARγ agonists) are important to induce antiproliferative or proapoptotic effects in cancer cells taking advantage of the inhibition of glycogen synthase kinase-3β (GSK-3β), a crucial activator of nuclear factor-kappaB (NF-kB), at the same time PPARγ agonists provoke several physiological modifications that influence lipid metabolism, glucose homeostasis and activation of inflammation signaling cascade  which is responsible of trapping and transforming glucose in glucose 6 phosphate (G6P); the phosphofructokinase 2 (PFK2) which, by generating fructose-2,6-bisphosphate , activates phosphofructokinase 1 (PFK1) to increase flux versus glycolysis; the pyruvate kinase M (PKM2) which promotes aerobic glycolysis etc. but all these enzymes are not so selective for tumoral cells and for most of them the anticancer agent developed is still of limited efficacy for the low tolerability in patients. Because lactate is excreted from the cell, inhibiting lactate production or lactate transport out of the cell are two strategies that directly target the Warburg effect in cancer. The family of monocarboxylate transporters (MCTs) comprises the major proteins that are responsible for lactate export in glycolytic cells, including cancer cells (Figure Worldwide, the prevalence of MetS is increasing, and in the United States, nearly two-thirds of adults are either overweight or obese. Given the rising epidemic of metabolic syndrome worldwide, especially in developing countries, and the potential links among MetS, obesity, androgen metabolism, diabetes, and inflammation, it is critical to better understand the complex relations between MetS and cancer risk and the role of chronic inflammation in MetS and the pathogenesis of cancer.Clearly, to dissect these interrelated factors, future prospective studies should be sufficiently large, with better assessment of overall and abdominal obesity and with biochemical measures, such as insulin concentrations, sex steroids, and IGFs, to clarify the complex interplays of these factors on cancer risk. Etiologic heterogeneity should be considered. Further refinement of molecular cancer classification, using biomarkers and genetic markers, coupled with a clearer understanding of the cellular and molecular pathways involved, should prove illuminating. Factors such as grade, stage, and aggressiveness of tumors should be assessed and incorporated into the analysis. Methodological studies are also needed to gain a better understanding of the determinants of these biomarkers, including insulin, leptin, adipokines, IGFs, sex steroids, and inflammatory mediators, and to provide biological data to help interpret the results.A potential role for IGF-IR target therapy, PPARs agonists, TZDs and metformin in the adjuvant treatment of cancers is advisable, but further studies are warranted in order to better clarify the impact of these drugs in cancer therapy. At the time of writing, nearly 60 patents have been filed for small-molecule activators of AMPK, and it is hoped that some of these may enter human clinical trials soon. It seems likely that by the end of this decade we will have a much clearer picture of whether drugs that are selective for MetS will have a place in the treatment of cancer.


The lower incidence of breast cancer in Asian populations where the intake of animal products is lower than that of Western populations has led some to suggest that a vegetarian diet might reduce breast cancer risk.Between 2011 and 2014 we conducted a multicentre hospital based case—control study in eight cancer centres in India. Eligible cases were women aged 30–70 years, with newly diagnosed invasive breast cancer (ICD10 C50). Controls were frequency matched to the cases by age and region of residence and chosen from the accompanying attendants of the patients with cancer or those patients in the general hospital without cancer. Information about dietary, lifestyle, reproductive and socio-demographic factors were collected using an interviewer administered structured questionnaire. Multivariate logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals for the risk of breast cancer in relation to lifelong vegetarianism, adjusting for known risk factors for the disease.The study included 2101 cases and 2255 controls. The mean age at recruitment was similar in cases (49.7 years (SE 9.7)) and controls (49.8 years (SE 9.1)). About a quarter of the population were lifelong vegetarians and the rates varied significantly by region. On multivariate analysis, with adjustment for known risk factors for the disease, the risk of breast cancer was not decreased in lifelong vegetarians (OR 1.09 (95% CI 0.93-1.29)).Lifelong exposure to a vegetarian diet appears to have little, if any effect on the risk of breast cancer. Breast cancer is the most commonly diagnosed cancer in women globally, with approximately 1.67 million cases in 2012 [The lower incidence of breast cancer in Asian populations where the intake of animal products is lower than that of Western populations has led some to suggest that a vegetarian diet might reduce breast cancer risk .Diet related factors which have established associations with breast cancer risk include alcohol consumption and obesity , 5. TherIndia provides a unique opportunity to examine the role of diet in relation to cancer risk, as vegetarianism in India is associated with unique characteristics in that it is usually a lifelong pattern and of a much higher prevalence than in the West where most studies examining this association have been set . We repoBetween 2011 and 2014, a multicentre case—control study was conducted in eight participating hospitals in India  diagnosed within the preceding six months and presenting to the hospital for diagnosis and/or treatment. Patients with a past history of breast cancer were excluded, but patients with a first presentation of metastatic breast cancer were eligible for participation. Two groups of hospital based controls were used: (1) women without a diagnosis of cancer who were accompanying cancer patients and (2) women who had been admitted to the hospital with illnesses not related to the exposure of interest e.g. trauma. Approximately 80% of the controls were accompanying cancer patients with the majority accompanying non breast cancer patients.All controls were frequency matched to cases by age  and state of residence ; the interaction between parity and duration of breast feeding ; as well as self-reported location of house  and the presence of running water in the house (no/yes), which were used as indicators of socioeconomic status.A logistic regression model was used to examine the association between risk of breast cancer and lifelong vegetarianism. The model was stratified by age (in 10 year age groups) and state of residence, to account for frequency matching, and adjusted for known risk factors. These included body mass index (BMI) before illness  and 95% confidence intervals (CI) are reported. Women with missing data for lifelong vegetarianism (1.1%) were excluded from the analysis. Women with missing values for a given adjustment variable  were assigned to a separate category for that variable, but these data are not shown. Statistical tests of heterogeneity across categories of a variable were performed using likelihood ratio tests.In this study, 33% of the controls reported to be accompanying a patient with breast cancer although they may not have necessarily been residing in the same dwelling. However, this might bias our results as individuals from the same household may share similar dietary patterns. To assess this possibility we performed a sensitivity analysis restricting the controls to those who did not report accompanying a patient with breast cancer.All data was entered centrally onto a custom designed database with internal validity checks. All analyses were performed at the University of Oxford using Stata V12.The study population consisted of 2 101 cases and 2 255 controls in the study and the characteristics of the study population are summarised in Table The mean age at recruitment into the study was similar in cases and controls (49.7 years versus 49.8 years). Approximately three quarters of the study population were housewives and four out of five participants were of Hindu religion. A higher proportion of the cases lived in a town or city compared to the controls (58% versus 50%), had running water in their property (84% versus 78%) and lived in a stone rather than mud house (88% versus 84%). Eighty-eight percent of both cases and controls reported having a self-contained toilet within their property.N = 611) and 25% of controls (N = 560). There was significant geographic variation with rates of over 70% in Rajasthan and Gujarat, and <10% in the north eastern state of Assam and in Kerala. In general among the LLVs, consumption of eggs was extremely low with only 3% (N = 31) reporting that they had ever eaten eggs. The consumption of both alcohol and smoking of tobacco was virtually non-existent, but around 10% of the study population chewed tobacco or non-tobacco products.The overall proportion of lifelong vegetarians in the study was 29% of cases (2 versus 24.6 kg/m2).The mean height of cases and controls was similar (154.5cms versus 154.0cms), but the mean body mass index (BMI) was higher among the cases  with mean number of years of breastfeeding of 3.9 years for cases compared to 4.4 years for the controls. The use of exogenous hormones, either oral contraceptives or hormone replacement therapy was virtually non-existent. About a third of the whole study population had undergone a procedure for sterilisation.The results of the multivariate analysis are shown in Fig. 2 was approximately twice that of women with BMI < 20 kg/m2 . Women who lived in villages had 27% less risk of breast cancer than those who lived in urban areas . The results of the sensitivity analysis showed that any bias caused by recruitment of attendants accompanying breast cancer patients was likely to be small. The association seen in the restricted analysis was not different to the main result seen in the full analysis for life long vegetarian diet and breast cancer risk .The risk of breast cancer in obese women with BMI >30 kg/mIn this multicentre case control study in India we find no evidence of an association between exposure to a lifelong vegetarian diet and subsequent risk of breast cancer, after adjusting for known risk factors.Lifestyle factors, including dietary patterns, have long been recognised as potentially important determinants of cancer risk. The interest in a possible association between diet and risk of breast cancer is stimulated by the observed lower risk of breast cancer in South Asian populations and in South Asian diaspora , 9. TherLarge prospective studies which have examined the effect of diet on breast cancer risk in Western populations have not shown any significant effect, with the overall risk of breast cancer being largely similar in women who consume either a non-vegetarian or vegetarian diet –8, 14. TAlthough studies in India and of South Asians residing in the United Kingdom have suggested a possible lower risk of breast cancer in vegetarians, the findings were non-significant as the studies have largely been small and underpowered –11. Our 2 (OR 2.06). India is currently facing a challenging public health problem regarding malnutrition, as rising rates of obesity are being seen in urban populations whilst undernutrition remains a challenge in rural parts of the country, and there is significant heterogeneity within the country of under and over nutrition. The mean BMI of the participants in this study was over 25, and probably reflective of the participating centres. Three of our participating centres are in the states of Tamil Nadu and Kerala, where rates of women being overweight or obese are among the highest in India, and none of our participating centres are in states where undernutrition is very high [Overweight and obese postmenopausal women are at an increased risk of breast cancer compared to women of normal weight in Europe , 18, 19 ery high , 16.Other lifestyle factors which are known to raise breast cancer risk in Western women include the consumption of alcohol  and use The single most important reproductive factor associated with breast cancer risk in this study was breastfeeding and substantial reductions in breast cancer risk were seen in women who engaged in longer durations of breast feeding, regardless of parity. The protective effect of breastfeeding on breast cancer risk is established, with approximately a 4% reduction in breast cancer risk per 12 months of breastfeeding and no significant differences are seen in the magnitude of the reduction in risk in women in developed and developing countries .The main strength of this study is that it was powered to examine the relationship between diet and breast cancer risk and the final numbers recruited were adequate to reliably examine the association, and to our knowledge this is the largest study conducted in India to investigate this association. Detailed information about known risk factors for breast cancer was also collected to enable appropriate adjustments to be made, and by comparing the distribution of these known risk factors to nationally available data, we have shown that the study population is representative. The main limitation of this work is that case controls studies are subject to recall bias and examining the relationship between diet and cancer risk using this study design is challenging. A cancer diagnosis may influence the dietary and lifestyle patterns of a patient. This should not be an issue for life-long vegetarians, but to minimise this source of bias we restricted recruitment to cases who had been diagnosed with breast cancer within the previous six months.We find that exposure to a lifelong vegetarian diet appears to have little, if any effect on breast cancer risk but established risk factors such as breastfeeding and body mass index are very important. The rising incidence rates of breast cancer in developing countries is a public health concern, and findings from studies such as these emphasise the importance of tackling public health challenges such as obesity, in order to prevent some of the growing breast cancer burden.


The number of breast cancer survivors has increased since 1990 due to advances in biomedical technology that lead to an increase in early diagnosis and treatment. Research on survivorship has focused on the psychological and treatment aspects of the disease. The goal of this study was focused on exploring the lived experiences of breast cancer survivors from diagnosis, treatment and beyond.To understand the lived experiences of women who are breast cancer survivors.A purposive sampling strategy was used to recruit participants from two Missouri cancer centres. A total of 15 women breast cancer survivors were interviewed.Three major themes emerged that described the lived experiences of the women. These were factors from the diagnosis and treatment management impacting survivorship, relationship and support system and implication of survivorship. Participants noted that coping with the diagnosis and treatment was a stressful journey and required lots of adjustment and changes. Some developed various techniques such as journaling their activities which provided comfort. In addition, support from family was shared as the key which gave them strength and courage through the different stages of treatment. However, they found it difficult to articulate what survivorship meant.Using in‐depth interview techniques, this study shed light on the experiences of women who were diagnosed with breast cancer and have completed treatment. They acknowledged frustration with their diagnosis and body changes. Support received from family and friends helped them cope through their treatment. However, they felt abandoned once the treatment phase was over and were uncertain what survivorhood meant to them. Breast cancer is the most frequent malignancy affecting women across all ethnic groups in the United States. In 2013, an estimated 232 340 new cases of invasive breast cancer were expected to be diagnosed among women.et al.et al.Despite the high number of breast cancer survivors, most of the qualitative research on survivorship has focused on the psychological and treatment aspect of the disease.How do stages of breast cancer diagnosis affect treatment options?What adjustments do breast cancer survivals have to make in their daily life?How do breast cancer survivors perceive quality of life after diagnosis and treatment?The University of Missouri Institutional Review Board (#1161517) approved the study. Each participant was informed about rights and principles of protection of human subjects, and each approved their participation with a written informed consent under the principle of full disclosure and received a copy of the consent form.All the women were recruited from two Missouri cancer centres through the ‘Look Good Feel Better’ (LGFB) group which is a free programme sponsored by the American Cancer Society that teaches beauty (feeling good and fabulous about one's appearance and self‐image during chemotherapy and radiation treatments) techniques to female patients with cancer in active treatment to help them combat the appearance‐related side‐effects of cancer treatment. The programme is open to all women with cancer and undergoing treatment throughout the United States.N = 15). The desire was to have a sample that represented a variety of perspectives but shared some common experiences. The link to the LGFB was the shared experience. Some diversity was sacrificed, but it was decided that a common connection, such as LGFB, was a way to explore how that commonality affected their lived experience. The aim of the purposive strategy was to recruit participants that represented a range of perspectives within the LGFB. A diversity of experiences was based on age at diagnosis, stage at diagnosis and length of survival at time of the interviews. The goal was to get a broad cross section of perspectives within this framework. There were two challenges to this sample frame. One, there were no participants we could identify who would participate in the study who were of low income and without insurance. At fifteen participants, it was clear that we had reached a level of saturation with the population of breast cancer survivors from our potential sample frame. We were no longer getting new information that contributed to our analysis of the breast cancer survivor experience. We could have continued interviewing, but it was clear that any new data were not likely to impact the key themes that had already emerged from the fifteen interviews. The inclusion criteria were women: (i) older than 18 years of age; (ii) English‐speaking; (iii) a diagnosis of breast cancer; and (iv) completion of treatment, surgery, chemotherapy and/or radiation.A purposive sampling strategy was used by researchers to recruit the participants  the first author who interviewed all participants transcribed tapes verbatim and the first level of analysis, (ii) the second author reviewed the codes and themes to ensure results were true representative of participants’ story/lived experiences, and (iii) authors met to explore differences and refine codes.Ten white and five black breast cancer survivors participated in interviews that lasted from 53 to 75 min. The age of participants ranged from 47 to 69 years. Of the fifteen women, three were diagnosed at stage 0 of the disease, one at stage I, eight at stage II and three women had stage III cancer. Seven women had been cancer free between 2 and 5 years, while eight reported between 6 and 19 years cancer free. All participants had at least a bachelor degree and a full‐time job  factors from the diagnosis and treatment management impacting survivorship, (ii) relationship and support system and (iii) implication of survivorship.(Pea)I just told them you know, I got a lump and it's getting bigger. Well that got them [because at that time], the lump I could feel was the size of walnut. According to the women, their prior knowledge and understanding of breast health helped them identify changes in their breast and to seek early medical treatment. Pea noted that her annual mammogram examination in July 2006 got rescheduled to October due to scheduling conflict and was about to be rescheduled again. However, she sensed something was not right with her breast.(Doreen)Well, I was 48 so I'm glad it [the new recommendation to wait until 50 to have a mammogram] wasn't in effect when I went through because it wouldn't have been detected…it wouldn't have been stage 0. The knowledge and understanding the women had about breast health and cancer became a source of hope and a type of empowerment for the study participants during the diagnosis and treatment management stages of their diagnoses. Doreen discussed the importance of the breast screening and annual mammogram in relation to the new United States Preventive Services Task Force (USPSTF) guideline, which recommended that women have an annual mammogram beginning at age 50 instead of 40, the previous guideline. Doreen believed that the younger age guideline of 40 helped save her life so she was highly critical of the change in the guideline to 50 recommended by USPSTF.(Piper)I was scared because you don't know what to expect, but you keep going… Stage at diagnosis and treatment options was another factor which impacted the women's recovery process. Participants indicated they were ‘shocked’ and ‘scared’ when they were informed about the diagnosis.(Jenny)I was just thankful that my cancer was so early, was so treatable. Stage at cancer diagnosis has an impact on an individual's prognosis and survivorship. Participants noted, once the diagnosis was certain they were grateful it was not an aggressive form of breast cancer.(Tracy)I was ready for the option of mastectomy and my doctor said, you don't need to be that radical, but it's your choice… I opted for mastectomy. While most participants shared that their cancer was not detected late, due to fear of recurrence, they chose the most ‘aggressive treatment’.‘humour’ in the process.The body changes experienced by the women were a challenge for them during treatment that several of the participants discussed. They stated that the hair loss was the aspect of treatment that disturbed them the most. It was highly detrimental to their ability to cope and negatively affected their self‐esteem. However, they tried to make the best of the situation and their efforts were illustrated by their resilience during the process. The women indicated it was not funny going through all these experiences, but they tried to find (Doreen)…I've heard of people who lost their business and so they are home for family member who had extensive cancer treatment. I didn't have any problem. It costs me very little. Cost of cancer treatment. All the women in this study had health insurance and were able to access medical care. Participants considered themselves lucky because they did not experience too many financial difficulties because their health insurance covered treatment cost.(Ashley)My life would have been very terrible. I think it makes it harder to make the same decision. (Rose)I will tell you though, if I didn't have insurance, I probably would not have a home right now. I mean, we couldn't have made the payments. All the women noted they could not have maintained the same quality of life, if they have not had full‐time job and health insurance that paid for the treatment. Nevertheless, they expressed concern for other women who faced the same problem without a job (with insurance) and money to undergo treatment.According to participants, coping with the diagnosis and treatment of breast cancer was ‘a very stressful journey’ for cancer patients and survivors; this is complicated by ‘fear, anxiety, grief and many emotional issues’. Coping in this context referred to their ability to successfully manage the stress and challenges associated with the diagnosis and treatment of breast cancer. To cope with their diagnosis and treatment required lots of adjustment and changes in order to effectively deal with physical symptoms and treatment impacts. Participants developed various methods that helped them keep their mind off their disease. Some mentioned that journaling their daily activities provided them comfort, while others were involved in various fun activities that helped them maintain positive attitudes.(Piper)…my husband was very supportive the whole time. (Pea)My husband was very supportive…he just treated it like I had cold. I am fortunate to have my family support…it's your immediate family that help you through the physical, through your condition, and also, believe it or not through your mental condition. (Keila)The incredible support that I had from my husband and my boys… makes the treatment itself bearable. The women indicated that support was a critical ingredient to their physical and mental health when they faced cancer care. Most essential was the support of family. Friends and co‐workers were also mentioned as very important as one went through the process. Some of these forms of support were nearly as important as family to several of the participants. These support systems provided the women with strength, courage and motivation to successfully manage and navigate the different stages of treatment and adjustments even after they were told they were cancer free. Family and friends support systems were reported by participants to be the most beneficial. A strong family support was the ‘key’ according to participants.(Rose)It was difficult to see younger individuals like 35 or 40 years who don't have a good prognosis like the older ones and have small kids to take care of. (Vivi)…those who have double mastectomy and numerous cancers and are aware they are gonna die; it was sad. As important as support system is, participants mentioned that not all support systems were helpful to them. For instance, Jenny mentioned she advised and encouraged her cousin to join a formal breast cancer support group when she [her cousin] was diagnosed with cancer, but her cousin would not participate. This frustrated Jenny because she could not understand why her cousin would not participate. But after Jenny was diagnosed with cancer, she realized formal support groups may not be as important as they were portrayed in the cancer social support literature. Several of the women shared a similar perspective. They mentioned formal breast cancer support groups were not required for ‘everybody but [worked for] a lot of people’. Several participants seemed to think that formal breast cancer support groups were important but not necessarily a good match for them. They preferred the support they got from family and friends. Some viewed these meetings as depressing.(Pea)…not just friends, but friends going through the same thing. Participants reported it was important for them to have friends going through the same situation at the same time.(Tracy)I had a girlfriend that was diagnosed two weeks before me and another girlfriend diagnosed two weeks after me. So it was the three of us. So if you got to feeling really down, you could call one of them… One woman shared that she and another participant became friends during their treatment process. They considered this to be like a sisterhood, creating a bond that would last for the rest of their lives. To them, it was valuable to have had this type of friendship rather than being part of a formal social support group. They shared that they did not need support groups because they went through the stages of the process together. When they were going through the stage where their hair was falling out, they had a hair shaving party together. They did things together throughout the entire process to provide mutual support. Other things included calling each other after chemotherapy and comparing notes.(Eve)I just hate the term warriors and the battle cry. Because it's like; what are you fighting? That's exhausting! (Vivi)I don't mind talking about it, but I don't know what to call myself. Survivorship is a unique journey and was viewed from a different perspective from survivor to survivor. Diagnosis with breast cancer caused the women in this study to appreciate and realize how ‘precious life is’ and the importance of living life one step at a time and to never to take each passing day for granted. Although the women fully accepted what they went through and were ready to share their experiences and insights on breast cancer, some of them were still not sure what survival meant, and felt they were not ‘quite there yet’.On the other hand, some of the women had fully embraced themselves as ‘warriors’ and are ‘grateful to God to be alive’. MaryAnn noted that to her, ‘Survivor means a day without cancer’.(Doreen)I will say it helped to [become] more centered. That I'm more in tune with myself and what I want to do and what I'm capable of doing. Others shared that to them survivorship meant development of new attitudes and perceptions about life in general.(Doreen)…I think that might be the extent of my helping raise funds right now. Another aspect of the survivorship journey participants shared focused on advocacy and foundation creation. Participants indicated that breast cancer is a disease that all women could identify with irrespective of age, colour and education. Many women in this study were involved with foundations and other projects to provide education, generate awareness as well as raise funds for breast cancer research. A few of the women who were participants of this study shared a desire to establish a foundation of their own but most did not. One participant, Doreen, expressed an interest in raising funds but was not interested in any activism beyond that:(Pat)I don't like to be in the lime‐light or anything like that. I will give money to a foundation towards breast cancer survivors. (Ashley)…I don't like to be reminded I've had breast cancer… A majority of the other participants were not all enthusiastic about creating foundations in their names. They believed in the principle of doing things in the ‘quiet’ rather than getting involved in activities for ‘splashy attention’. They shared that the creation of a foundation was not for them.The purpose of the study was to better understand what it meant to be a cancer survivor by exploring the lived experiences of women who were ‘cancer survivors’ as they moved through the diagnosis, treatment and recovery process. Several things emerged from this analysis that can provide insight as to what it meant to be a cancer survivor and how different elements of the treatment process affected their perceptions of the survival experience.Individuals who have lived past cancer are often referred to as ‘survivors’. Does every breast cancer women want to be called a survivor? Previous studies on survivorship reported that women embraced their new identity.In the present study, apart from one woman who embraced her new identity as a ‘warrior and survivor’, the rest of the women in this study did not see themselves as warriors/survivors, but were thankful to God they were cancer free. They found it difficult to articulate what survivorship meant. The women actually found the transition from being a ‘cancer patient’ to being a ‘cancer survivor’ very abrupt. One day, they were told they did not have to come back/as often, which resulted in a rather dramatic decline in their perception of the kind of support that would be available going forward. While the medical treatment may have been finished, the recovery process was obviously not complete for these women. The support they received from the health‐care providers changed, and in some cases, the expectations of family and friends also changed. They articulated a need for some support beyond post‐treatment to help deal with on‐going fear, and the transition to a more normal life. This finding was consistent with FrankIt was clear that managing fear was an important part of the diagnosis, treatment and recovery process. The breast cancer experience elicited many fears and concerns among the women interviewed as they progressed through the process. These included fears and concerns related to potential disfigurement from surgery, loss of body image, loss of sexuality and life after treatment, especially the possible recurrence of cancer. Learning how to manage the fear of recurrence was also part of what it meant to be a survivor. Some of the women chose to have more invasive surgeries because they were afraid of a potential recurrence of the cancer even when the medical staff assured them the probability was very low. They chose this option because they wanted to eliminate the risk to the greatest extent possible. They did not want to have to face the cancer again and chose the most extreme treatment possible even when the risk was low. This was also an option for them given they had the insurance and resources to make this choice.The women in this study expressed how important information and knowledge of breast cancer risks was to their decision‐making processes as they progressed through the treatment and recovery process. It helped them feel empowered to make the best decisions they could concerning their health. The women in this study stressed that women should never take their annual mammogram examination for granted. Several of the women fervently believed that their survival was enhanced because of their vigilance in terms of keeping up regular examinations. They also noted that when a woman chose to attend mammography, she voluntarily agreed to undergo breast screening. However, this did not imply that she has knowledge about her body. Participants mentioned it was required of all women to be familiar with their body in order to note changes and seek early medical attention. They found body knowledge empowering and several were diagnosed early because of the knowledge they had of their bodies. The process of becoming a cancer survivor reinforced this value and was a legacy of their survivorship.Consistent with the literature, social support was critical during the progress of diagnosis, treatment and beyond for the women.In contrast with previous findings on formal cancer support groups,Stage of diagnosis and treatment was another important theme that emerged. This was consistent with the literature which stated, cancer treatment and survival depended largely on the stage and prognosis of the disease.et al.,et al.et al.The physical change in appearance, specifically the hair loss (eyelashes and eyebrow), was a major negative factor affecting the ability of these women to effectively cope in the initial stages of their diagnoses and treatment. This was similar to what was reported by Doumit Cancer patients whether insured or not face significant and sometimes devastating hurdles in regard to receiving timely and affordable treatment.Much of the breast cancer research has focused on the physical aspects from medical perspective without addressing the stories of the survivors’ lived experiences. Using in‐depth interviews, and listening to women, we have shared their experiences with diagnosis, treatment and life after cancer. This study therefore serves as a tool to voice the lived experiences of these women by enhancing our understanding of the challenges these women faced as they completed the treatment process and continued their lives as ‘survivors’. It was clear from the stories they shared that survivorship included learning how to live with the experience and manage the fear of recurrence, which according to these women never goes away. Another implication of this study relates to education and counselling. Most of the women interviewed in this study did not want to be called breast cancer ‘survivors’ or ‘warriors’ which is a common term for someone who has been diagnosed and treated for breast cancer. For breast cancer educators and counsellors, this study hopes to further their knowledge and understanding regarding the use of the word survivor when counselling women who have experienced the disease or have completed treatment and were cancer free. The transition from cancer patient to cancer survivor has not been viewed as a process. Clinically, when the cancer is gone, then the patient is finished. However, the women expressed a sense of abandonment as a result. Additional work needs to be done to better understand how to effectively help women transition from a treatment phase into a recovery phase that helps them better manage life after cancer because the process haunted many of these women long after the cancer was gone.The main limitation of this study is that the experiences associated with these women may not reflect the experiences of all breast cancer survivors. All participants in the study are well‐educated, have stable families, economic resources and health insurance and did not experience much financial difficulties regarding cost of treatment that many women face which points to the need to broaden the scope of this work. One of the challenges as a researcher is to reach the women who are difficult to access. For those without insurance, their lack of resources and marginalization in the health‐care system made it much more difficult to engage them in this type of research process.According to FrankNone.None declared.


VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI) and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR. A reduced risk has been reported for the BsmI BB genotype which may influence VDR mRNA stability.The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The activity of 1,25-dihydroxyvitamin D3 is mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene polymorphisms are associated with breast cancer risk in Kazakhstan women.We have investigated whether specific 315) and a female control group (n=604) were tested for two VDR polymorphisms. Statistical analysis was conducted using SPSS19.0.In a case–control study, female breast cancer patients (: The VDR rs2228570 (FokI) polymorphism was associated with an increased occurence of BC . No association was noted between rs1544410 (BsmI) BB and breast cancer risk .: Although the factors that increase breast cancer susceptibility remain uncertain, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. Additional testing on the effect of varying genotypes on the functional mechanisms of the VDR could help to improve future testing and treatment of woman at risk for breast cancer.


This article aims to review both the pathological and biological evidence implicating a key role for the breast stromal compartment in MD, how this may be modified and the clinical significance of these findings. The epidemiological context will be briefly discussed but will not be covered in detail.There is strong epidemiological data indicating a role for increased mammographic density (MD) in predisposing to breast cancer, however, the biological mechanisms underlying this phenomenon are less well understood. Recently, studies of human breast tissues have started to characterise the features of mammographically dense breasts, and a number of  Mammographic density (MD) refers to the proportion of a mammogram occupied by radiologically dense fibroglandular tissue and is a major independent risk factor for breast cancer. A comprehensive meta-analysis of 14,000 cases observed that women with > 75% breast density had 4-6 times the risk of developing breast cancer compared to women with breasts of the lowest 25% density . High MDMD appears to be highly heritable; studies of twins have attributed up to 65% of the variation in MD to genetic factors  with theThe majority of studies investigating the genetic contribution to MD have focused on investigating the single nucleotide polymorphisms (SNPs) associated with increased breast cancer risk and their relationship with MD. So far SNPs in the region of ESR1, CCDC170, EBF1, LSP1, MIR1972-2:FTO, RAD51L1, ZNF365, MKL1, TNRC9/TOX 3, NTN4, NEK10, TAB2 and loci at 2p24.1 and 12q24 –14 have A key feature of MD compared to other established risk factors for breast cancer is that it is dynamic and modifiable. This modifiability offers significant therapeutic potential in the form of cancer prevention strategies targeted to reduce breast density. MD typically decreases with age, whereas breast cancer incidence conversely increases with advancing age. The Pike model attempts to resolve this apparent paradox by suggesting that cumulative lifetime exposure of the breast to dense tissue and associated growth factors and hormones, also referred to as ‘breast tissue ageing’, confers the age-related risk of developing breast cancer .This is reflected in the apparent hormonally responsive nature of MD; women with known risk factors for breast cancer related to prolonged oestrogen exposure, such as late first pregnancy and early menarche, show a higher degree of MD. In addition, the use of combined hormone replacement therapy also increases MD , 19. ConGiven that MD appears to be hormonally responsive, one might expect high MD to predispose to the development of oestrogen receptor (ER) positive tumours, however to date studies have reported inconsistent findings. McCormack and dos Santos Silva have recently performed a systematic meta-analysis incorporating over 24,000 cases, finding a similar magnitude of association with ER+ and ER- tumours and no difference in the association with human epidermal growth factor receptor 2 (HER2) status .Tamoxifen is a selective oestrogen receptor modulator, demonstrated in the IBIS-1 study to reduce MD and breast cancer risk . A furthPresently the mechanisms conferring susceptibility to the protective effect of tamoxifen treatment remain unknown, however, an association of cytochrome P450 2D6 (CYP2D6) metabolizer status with MD change in response to tamoxifen has recently been reported .In an animal model of breast cancer, tamoxifen treatment initiated remodelling of the mammary stroma to a tumour inhibitory phenotype with lower levels of fibronectin and reduced extra-cellular matrix (ECM) turnover . FurtherMD reflects variations in the tissue composition of the breast and is positively associated with collagen, epithelial and stromal cells and negatively associated with fat . Stroma A comprehensive study by Li and colleagues examined histological features of breast tissue obtained at forensic autopsy . They foIt has been hypothesised that MD may represent the influence of local oestrogen production on the breast . HoweverDespite the association of stromal content and high MD breast tissue, there is no standardised approach to measuring MD in histological sections. This, combined with the fact that MD is often heterogeneous in nature throughout the breast, poses a significant challenge to the planning of translational studies using human tissue.Whilst there is a strong clinical correlation, MD has not yet been causally linked to tumour formation and there have been a limited number of studies investigating the biological pathways mediating MD. Given that the stroma forms the major constituent component of dense breast tissue, the pathways contributing to the density-associated breast cancer risk are likely to involve the stromal cells, ECM proteins, and their interaction with the epithelial component.via multiple diverse mechanisms including the influence of growth factors secreted by cancer associated fibroblasts and remodelling of the ECM [The stromal microenvironment is known to have an important role in the progression of established invasive breast cancer , acting  the ECM , 49. In  the ECM , respons the ECM  and endo the ECM . Similarin-vitro work from another group who have observed that cell density, shape and ECM proteins are capable of inducing stromal aromatase expression [It has been hypothesised that in areas of high MD, abundant stromal fibroblasts may aberrantly secrete growth factors and hormones/cytokines that stimulate epithelial cell proliferation , 53. Onepression , thus prIt has been suggested that increased collagen production by stromal fibroblasts contributes to a stiffer ECM. The inability of normal breast epithelium to contract stiff matrix causes a tensional imbalance, reflected by altered signalling pathways that have the potential to induce epithelial cell proliferation .tmJae transgene which reduces collagen proteolysis, and examined the propensity for tumour formation with increased mammary collagen. They observed that higher stromal collagen density in mouse mammary tissue resulted in a threefold increase in tumour number and that the tumours which developed displayed a more invasive phenotype with greater local invasion and metastasis. The authors propose a functional link between increased stromal collagen density and breast cancer initiation and progression [Patricia Keely and colleagues developed a bi-transgenic mouse to model high breast density, utilising the Col1a1gression .Two possible mechanisms are suggested by which increased collagen density might promote tumour development. The first is a direct effect of increased matrix stiffness, resulting in a higher mechanical force and resistance to contractility on the epithelial cells. These forces might alter focal adhesion and Rho GTPase (Rho) signalling, resulting in increased proliferation . The secFurther work by this group examined whether collagen density alone, in the absence of fibroblasts, could alter mammary epithelial cell behaviour in 3D culture models. Supporting this hypothesis, greater collagen density alone increased matrix stiffness and promoted epithelial cell proliferation and invasion . They shThe authors propose that continued mechanical stimulation from a dense stromal matrix results in sustained activation of FAK-Rho signalling which, in turn, up-regulates other pathways such as Ras- Mitogen activated protein kinase (MAPK). ERK acts as a crucial bottleneck, regulating the response and inducing transcription of proliferation associated genes.via inhibition of notch homolog 1 (NOTCH1) [Soon et al examined the effect of high density collagen matrices on mammary epithelial cell behaviour. They found that high density matrices up-regulated the expression and activity of Rho-associated coiled-coil-containing protein kinase 1 (ROCK 1) (NOTCH1) . ROCK- 1As well as collagen density, the significance of collagen fibre alignment within the ECM in facilitating mammary tumour cell invasion has also been investigated by the Keely group . Collagein-vitro and tumourigenesis in-vivo [Weaver and colleagues have investigated how collagen cross-linking mediated by lysyl oxidase (LOX), a family of ECM cross-linking enzymes, can influence mammary epithelial cell behaviour. They used the MMTV-Neu mouse model of breast cancer to show that fibroblasts overexpressing LOX form a stiffer mammary fat pad and promote the growth and invasion of premalignant mammary epithelial cells. Similarly, inhibition of LOX resulted in a less stiff matrix and reduction in tumourigenesis . LOX-med in-vivo . Thus it in-vivo , has bee in-vivo  and is p in-vivo .More recent work by the same group, focusing on the molecular determinants of mammary epithelial cell mechanotransduction, has highlighted a crucial role for the focal adhesion component vinculin in translating the mechanical cues from a stiff ECM into tumour promoting intracellular signalling pathways . It is svia integrin-dependent activation of β-catenin and MYC. miR-18a subsequently interacts and inhibits expression of the tumour suppressor gene PTEN, which itself is a negative regulator of PI3-K activity - previously demonstrated as a key pathway promoting mammary epithelial cell malignant progression [via decreasing levels of homeobox A9 (HOXA9)  signalling. The activated JNK-1 stress signalling mediates the onset of a ‘myofibroblast’ phenotype characterised by ongoing inflammation and fibrosis, resulting in pro-tumourigenic, high density stroma [In addition, when the high density fibroblast gene signature was compared to the profile of tumour stroma, c-Jun N-terminal kinase 1 (JNK-1) stress signalling emerged as the most significant biological process shared between the two data sets . The auty stroma . The autWhether such markers of an activated stroma could be used to measure patient risk and as indicators of response to treatment strategies is an intriguing possibility.Martin and Boyd have proposed that the combined effects of cell proliferation (mitogenesis) and genetic damage to proliferating cells by mutagens (mutagenesis) may account for the increased risk of breast cancer with high MD ; a hypotThese data further emphasize the importance of stromal biology in mediating MD. The revised Martin and Boyd model incorporates and highlights the role of the stromal microenvironment in breast tumourigenesis.Reduced TGF-β signalling in dense breast tissue has also been observed by Yang and colleagues who compared gene expression in high and low density non-tumour breast tissue taken 5cm away from invasive carcinoma . A numbeA summary of our current understanding of the complex stromal biological pathways conferring MD-associated breast cancer risk is displayed in Figure Despite the progress made in these preclinical studies towards identifying potential stromal markers and signalling pathways contributing to breast density, this has not readily translated into clinically relevant markers or targets. Further clinically applicable approaches are needed to identify the key stromal molecules driving density-associated risk in humans.The influence of MD on breast cancer risk has a number of important clinical implications, particularly with regard to identification of high risk individuals, screening and prevention. Four studies have investigated whether including a measure of MD improves risk estimation compared to standard risk models –80. All Screening at more frequent intervals with more than one imaging modality may be appropriate for women with dense breasts due to their increased risk of developing cancer and their increased risk of tumour ‘masking’. A recent analysis of personalised mammographic screening according to MD, age, family history and history of breast biopsy was found to be cost effective .It has been postulated that change in MD could be used as a marker in clinical trials evaluating breast cancer prevention strategies . This coMD is more strongly associated with breast cancer risk than other variables such as family history and reproductive factors. Therefore, knowledge of an individual's mammographic density and in particular, their expression levels of genes coding for ECM proteins and other stromal biomarkers, may allow individual risk prediction for breast cancer. MD also offers the advantage over other breast cancer risk factors of being modifiable, which provides exciting potential for therapeutic intervention to reduce both MD and breast cancer risk.Targeting components of the microenvironment is already an established strategy in the adjuvant treatment setting for a number of different tumour types , 84. Thevia integrin inhibition is also the subject of clinical trials with agents showing limited anti-tumour efficacy at present [Components of tumour-associated inflammation are also a focus of new agents targeted against the microenvironment. An interleukin 6 (IL-6) neutralising antibody is currently undergoing evaluation in clinical trials , and neu present , 91. Spe present , utilisi present , and vac present .Harnessing similar approaches in the preventive setting to target the stromal molecules and pathways mediating MD could provide an effective cancer prevention strategy. Thus, further work to dissect the complex biological pathways mediating MD is urgently needed to identify novel, clinically relevant, biomarkers driving the density-associated risk.