This study aimed to determine the relationship between rs17576 (MMP-9) polymorphism and increased cancer risk in a Brazilian breast cancer cohort.This study included 141 women (71 breast cancer patients and 70 controls without breast cancer) who donated 3 mL of their peripheral blood for genomic DNA extraction. This DNA was then genotyped using a real-time polymerase chain reaction.p=0.274), while the GG genotype was identified in ten (7.09%) participants in the case group and in one (0.70%) participant in the control group (p<0.003 - OR (95% CI) 13.13 . No significant difference in the incidence rates was observed for AG or GG rs17576 genotypes in premenopausal women, p=0.813 and p=0.556, respectively. However, in postmenopausal women, the AG genotype was shown to occur in 14 (22.5%) participants in the case group and in 4 (6.45%) participants in the control (p<0.043), while GG genotype occurred in eight (12.90%) of the individuals in the case group and in none of the individuals in the control group (p<0.006).The AG (rs17576) genotype was identified in 26 (18.43%) participants in the case group and in 22 (15.60%) participants in the control group (In this study, the MMP-9 rs17576 GG polymorphic variant was shown to be significantly associated with breast cancer risk in premenopausal women, while the AG and GG genotypes were associated with increased cancer risk in postmenopausal women. Breast cancer is the second most common malignant neoplasm in the female population of Brazil after non-melanoma skin cancer, with an estimated 59,700 new cases and 14,206 deaths in 2018  have been linked to increased risk of developing breast cancer. MMPs are a family of zinc-dependent proteinases that are all structurally and physiologically related based on their ability to degrade the extracellular matrix (ECM) . In vivot effect ,5.MMP-9) gene encodes an enzyme that hydrolyzes ECM components and assumes a primordial function during tissue remodeling, resulting in angiogenesis and metastases . Patients were excluded from the study if they were affected by any other type of cancer or if they were over 80 years old. All study participants signed an informed consent prior to the initiation of our investigations. Our research protocol complied with the Resolution 466/2012 proposed by the Brazilian National Health Council and was approved by the Research Ethics Committee at the Federal University of Piauí, Teresina, Brazil (CAAE 43447015.8.0000.5214). This study was compliant with the terms established in the Declaration of Helsinki (1964) and its later amendments or other comparable ethical standards.® Blood&Tissue Kit (QIAGEN®), as per the manufacturer’s instructions. Qualitative and quantitative estimation of the DNA in each sample was performed using a Nanodrop 2000 spectrophotometer . The concentration of all DNA samples was adjusted to 20 ng/µL before genotyping and the DNA samples were stored at -20°C for long-term storage.A 3 mL aliquot of whole peripheral blood was collected and stored in appropriate bags containing (EDTA) anticoagulant solution at -20°C. Genomic DNA was extracted from 200 µL of whole blood, using the DNeasyGenotyping was performed in the Molecular Biology laboratory at the Institute of Tropical Diseases under the guidance of Dr. Natan Portela, Teresina, Piauí, Brazil, using real-time polymerase chain reaction (RT-PCR). Amplification was performed on the Fast RT-PCR System 7500 with SDS 2.2 software for SNP genotyping .® Genotyping Master Mix; 0.5 µL of the TaqMan® custom probe for SNP genotyping of human MMP-9 (SNP ID rs17576. Cod. C__11655953_10)  ; 5.5 µL t-test was used to compare the age of the groups and subgroups. Chi-square test was used to determine whether genotype distribution was in agreement with the Hard-Weinberg equilibrium and the genotype frequency was compared between breast cancer patients and the control group , using a Fisher’s exact test as described by Agresti & Kateri (11). The odds ratio (OR) and 95% confidence interval (CI) were calculated using a Fisher’s exact test because of the low frequency of several of the variations. A Pearson's test was used to assess the correlation between various clinical features and the MMP-9 rs17576 genotype. Significance was set at p<0.05.p=0.2746), while the GG genotype (rs17576) was identified in ten (7.09%) women in the case group and in one (0.70%) woman in the control group (p<0.0030 - OR (95% CI) 13.13 ) (This study included 141 women (71 cases and 70 controls) and the mean patient age in the cancer group was 49.9±12.03 years (27/76), while in the control group the mean age was 45.3±12.77 years (18/78). No significant difference was observed between the mean ages of any of the groups or subgroups evaluated in this study . The gen593.08)) .p=0.8132) and GG genotypes  were not found to be significantly associated with breast cancer risk in premenopausal women when compared to wildtype (AA). Conversely, there was a significant difference in AG and GG genotype frequencies in postmenopausal women with and without breast cancer, p<0.043 and p<0.0065, respectively   and the genotypes identified in these groups  and no lymph node metastasis (n=29) . Okada eIt is noteworthy that there is evidence indicating that MMP-9 rs17576) genotypes and haplotypes affect MMP-9 expression in obese children and in patients of African descent, suggesting that they may exert different effects, resulting in different and varied pathologies 576 genot. MoreoveDespite the controversial data in the literature regarding the association between rs17576 and breast cancer and other types of cancer, this study sought to evaluate the role of this SNP in the Brazilian population. This study is limited by the small number of studies and patients analyzed, which makes it more difficult to better characterize the involvement of the rs17576 locus in cancer risk, especially in breast cancer patients.In summary, the results of this study show a significant association between MMP-9 rs17576 (GG) genotype and breast cancer risk. In addition, AG and GG genotypes of MMP-9 rs17576 are both associated with increased cancer risk in postmenopausal women. There is a need to validate these findings in a larger cohort, especially in a country known for its genetic diversity.V.A. Oliveira, J. R. Amorim, D.C. Chagas, R.O. Pereira, L.M. Campos-Verde, T.A. Nogueira, V.M.L Borges, L.M. Martins, G.P. Rodrigues, E.J.N. Júnior, F.A. Sampaio, P.V. Lopes-Costa, J.M.C. Sousa, V.C. Silva, F.C.C. Silva, and B.B. da-Silva contributed to the conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing-original draft, and writing/reviewing and editing.


Diet quality is known to influence cancer risk. The Healthy Eating Index (HEI) is one of the most frequently used measures of diet quality. However, the association between HEI-2015 and breast cancer risk is not known. The present study was undertaken to evaluate the association between HEI-2015 and breast cancer risk. A case-control study comprising 134 breast cancer patients and 265 cancer-free controls were conducted. Dietary intakes were assessed using a validated food frequency questionnaire (FFQ), from which the HEI-2015 score was calculated. Logistic regression was used to derive the odds ratios (ORs) for measuring the association between HEI-2015 scores and breast cancer risk. Subjects in the top quartile of HEI-2015 had a 46% lower chance of breast cancer compared with subjects in the bottom quartile . After adjustment for potential confounders such as age, age at menarche, oral contraceptive drug use, menopausal status, marital status, body mass index, smoking and education level, the association between HEI-2015 score and a lower risk of breast cancer was enhanced . We successfully demonstrated that a higher HEI-2015 score was associated with a reduced breast cancer risk.  Breast cancer (BC) is the most common type of cancer among women, both in terms of incidence and mortality . In 2012 alone, approximately 1.7 million women were diagnosed with BC globally. This figure is expected to rise steadily to 3.2 million in year 2050 . Currently, the incidence of BC in western countries is higher than in Asian populations, but the rate is increasing at an alarming rate in Asian countries . In Iran, the incidence of BC is about 22 cases per 100,000 women . Several risk factors have been unequivocally associated with cancer incidence, including non-modifiable factors such as genetics, age and gender, and modifiable factors such as the food and the diet . For example, it has been shown that foods rich in phytochemicals and antioxidants, and low in saturated and trans fatty acids, have protective effects against cancers . More recently, a link between the quality of the overall diet and cancer risk has been suggested. The Healthy Eating Index (HEI) is one of the most commonly used measures of diet quality . The HEI is updated every five years, with the most recent update made in year 2015 (HEI-2015). The HEI-2015 assesses diet quality based on the intake of 13 components, namely total fruits, whole fruits, total vegetables, greens and beans, whole grains, dairy, total protein foods, seafood and plant proteins, fatty acids, refined grains, sodium, added sugars and saturated fats . It has been shown that there is a relationship between the HEI scores and the development of some types of cancer . Individuals with a high score in HEI are generally less prone to cancer development . However, to date, there has been no study evaluating the association of the HEI-2015 scores with breast cancer risk. Therefore, the present study was undertaken to evaluate the association between the HEI-2015 scores and breast cancer risk.Study designA case-control study involving 134 women with BC and 265 cancer-free controls were conducted. Cases were women aged 30-65 years, who were histologically confirmed as having BC  within 5 months from the recruitment date. All cases were recruited from the general hospital of Tehran, Iran. Patients with a history of any cyst or cancer (except the current BC) and those who were under hormone replacement therapy were excluded. Controls were age-matched women recruited from other wards of the same hospital with no history of cysts, cancer, or hormone replacement therapy. All participants (cases and controls) were excluded from the study if their reported energy intake was ≤ 500 Kcal/day or ≥ 5,000 Kcal/day. In addition, participants who skipped ≥ 50 items in the food frequency questionnaire (FFQ) were excluded from the study. Nine participants from the control group withdrew from the study and one was excluded due to the incomplete food item records. All participants signed a written informed consent form before enrolment into the study. The study protocol was approved by the Research Institute for Nutrition and Food Sciences, Shahid Beheshti University of Medical Sciences.Dietary assessmentThe dietary records of the participants were collected by trained dietitian interviewers. A validated FFQ consisting of 168 items was used to collect dietary information semi-quantitatively . The interviewers recorded dietary intake of each food item on the basis of daily, weekly and monthly frequency. The portion sizes of selected food items were determined based on the US Department of Agriculture portion sizes and household measures and were then converted to grams . Healthy Eating Index-2015 (HEI-2015) score calculationThe HEI-2015 comprised 13 components, namely 1) Total Fruits; 2) Whole Fruits, 3) Total Vegetables; 4) Greens and Beans; 5) Total Protein Foods; 6) Seafood and Plant Proteins; 7) Whole Grains; 8) Dairy; 9) Fatty Acids; 10) Refined Grains; 11) Sodium; 12) Added Sugars; and 13) Saturated Fats. The first six items carried a maximum of five points each while the other items carried a maximum of ten points each. In order to calculate the scores of the HEI-2015, amounts consumed from each food item were acquired from FFQ and food groups were converted to cup and ounce equivalents. The ‘Total Protein Foods’ consisted of servings of meat, poultry, seafood, eggs, legumes, seeds, nuts (beans and peas) and soy products. The ‘Total Fruits’ component included servings of whole fruit and fruit juice. The ‘Seafood and Plant Proteins’ included servings of seafood, seeds, nuts, legumes (beans and peas) and soy products. The ‘Whole Grain Foods’ consisted of servings of legumes (beans and peas) and dark-green vegetables while the ‘Total Vegetables’ comprised servings of legumes (beans and peas), dark-green vegetables, and all other vegetables. The ‘Fatty Acids’ was considered as a ratio of polyunsaturated (PUFA) and monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA). The ‘Saturated Fats’ and ‘Added Sugars’ were transformed to the percent of total energy intake and the rest of the food ingredients were transformed to the amounts per 1,000 kcal except for Fatty Acids. The range of the HEI-2015 score was between 0-100.MeasurementsThe weight of the participants was measured to the nearest 0.1 kg using a digital scale  on a flat and uncarpeted surface with minimum clothes and without shoes. The height was determined using a stadiometer  to the nearest 0.5 cm without shoes. The BMI was calculated by dividing weight in kg to height squared in meters. The level of physical activity during the past year was determined using a validated questionnaire (IPAQ) during the interview and was expressed as metabolic equivalent hours per day (MET-h/day).Statistical analysisIn order to determine the difference in general characteristics between cases and controls, analysis of variance (ANOVA) and chi-square tests were used for continuous and categorical variables, respectively. The participants were assigned to a quartile according to their scores on HEI-2015. The means of age, weight, height, BMI, energy intake and HEI scores were specified across the quartiles using the general linear model. The association between the HEI scores and breast cancer risk was determined using multivariable logistic regression models across the quartiles. The model was adjusted for confounding variables such as age (y); BMI (kg/m2); educational level (y); occupation (housekeeper/ employee/ retired); use of alcohol and tobacco (yes/no); age at menarche (y); marital status ; age at first pregnancy (y); number of full pregnancy; menopause status (yes/no); family history of breast cancer (yes/ no); use of OCP (yes/no); use of bra ; life satisfaction (yes/no/partly); physical activity (MET-h/ week); energy intake ; energy density of diet .In order to determine the trend of the association across specified quartiles of the HEI scores, the median of each quartile was used as a continuous variable in the logistic regression model. All statistical analyses were performed using SPSS . A p-value of <0.05 was considered statistically significant. General characteristics of the cases and controls are shown in Usual intakes of selected food and nutrient groups in cases and controls are provided in The association between the HEI-2015 scores and breast cancer risk is summarized in Over the past decades, nutritional epidemiological studies have identified a number of food or nutrients which could affect the risk of breast cancer, but the results remain inconsistent . One explanation for the inconsistency in the study findings was that the effect of a single food or nutrient could be easily reversed by another food or nutrient . Thus, modern nutritional epidemiological studies have focused on assessing the effect of the overall diet quality in order to better capture the dietary variability in the population. The Healthy Eating Index (HEI) is one of the most commonly used measures of the overall diet quality . In this work, we investigated the association between the HEI-2015 scores and breast cancer risk. A high HEI-2015 score indicated a high intake of fruits and vegetables, whole grain, dairy products, protein and unsaturated fatty acids, while a low score indicated a high intake of refined grains, sodium, added sugars and saturated fats . We observed that high HEI-2015 scores were significantly associated with a decreased risk of breast cancer. This association was strengthened after adjustment for various risk factors of breast cancer, suggesting that the observation was robust. Fruits, vegetables and whole-grain are rich in bioactive substances such as vitamins and carotenoids which possess antioxidant properties; thus, it is not surprising that a high intake of these foods can prevent cellular damage by free radicals and lead to a reduction in breast cancer risk . In addition, fruits, vegetables and whole-grain have a high content of dietary fiber and other nutrients that can reduce the levels of estrogen and N-nitroso compounds as well as increase the levels of anti-inflammatory cytokines, which collectively prevent breast cancer initiation and progression . On the other hand, dairy products are double-edged swords in regard to their effect on cancer risk. While some evidence suggested that dairy products contain high amounts of calcium and vitamin D which can bind to cancer-causing acids and metabolites to reduce breast cancer risk , some other evidence found that dairy products may increase cell proliferation due to their high levels of growth-promoting factors such as insulin-like growth factor 1 (IGF-1) . Besides, unsaturated fatty acids can decrease the levels of free radicals and alter estrogen metabolism, which protects against cancer development . These observations explain why a higher HEI-2015 score was associated with a lower risk of breast cancer as noted in the present work.There are a few strengths and limitations of the present study. A major limitation was that there could be recall bias among the participants as the study was retrospective in design . However, the recall bias is likely minimal as the dietary data was collected by trained dietitian interviewers using a validated FFQ. Another limitation of the present study was the modest sample size. Despite this, the study has generated important data that could serve as a solid foundation for future research in this area, which represents one of the major strengths of this study. In fact, to the best of our knowledge, this is the first study that investigated the association between HEI-2015 scores and breast cancer risk. In addition, we adjusted our study findings for many potential risk factors of breast cancer, which ensured that our study finding was not affected by potential confounders.In conclusion, the present work has successfully shown that a high HEI-2015 score was associated with a reduced risk of breast cancer. Our finding suggests that an overall healthy diet is important for the prevention of breast cancer; thus, a diet rich in fruit, vegetables, whole grains, dairy products and unsaturated fats should be encouraged. Nonetheless, future studies, especially prospective cohort studies, are warranted to confirm our findings.


These results suggest that the risk associations reported for BBD subtypes in the pre-mammography era remain valid for BBD detected after the widespread implementation of mammographic screening.Data on the risk of breast cancer following a benign breast disease (BBD) diagnosis were derived predominantly from populations of women biopsied before the widespread use of mammographic screening and in whom these lesions were mostly incidental findings. Whether or not similar risk associations are seen when these lesions are detected in mammographically screened populations is unknown. To address this, we examined the variation in BBD and breast cancer risk associations by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) in a nested case–control study within the Nurses’ Health Study (NHS) and NHSII BBD subcohort . We performed logistic regression analysis, adjusting for matching factors and potential confounders, to estimate odds ratio (ORs) and 95% confidence interval (CI) for the association between BBD subtype ) and subsequent breast cancer risk. When compared with non-proliferative lesions, both proliferative lesions without atypia (PWA) and AHs were associated with similar levels of risk in the pre-mammographic (pre) and post-mammographic (post) time periods . The interaction by mammography era was not statistically significant ( However, these data were derived from populations of women who, for the most part, were biopsied before the widespread use of screening mammography and in whom these lesions were incidental findings in the context of a clinically symptomatic lesion, most often a palpable mass, that was surgically excised5. It is unknown whether the BBD risk associations based on biopsies performed in the pre-mammography era4 are applicable to the BBDs detected in biopsies performed for a non-palpable lesion detected by screening mammography. This is an important clinical question that could have a significant impact on individual patient counseling, risk estimation models, and design and evaluation of preventive interventions.Benign breast disease (BBD) is a term that encompasses a heterogeneous group of lesions with different levels of subsequent breast cancer risk. To date, most epidemiologic studies, including studies from our group, have shown that proliferative lesions without atypia are associated with a 1.5- to 2-fold increase in breast cancer risk, whereas atypical hyperplasias are associated with a 4–5-fold increase in riskIn this study, we examined whether the associations of BBD subtype  with breast cancer risk were similar between the pre- and post-mammography era (before vs. 1985 and after). We also examined whether the associations vary by BBD detection method (mammogram vs. self-exam/physician’s exam). For these analyses, we used a nested case–control study within the Nurses’ Health Study (NHS) and NHSII BBD subcohort. Because mammographic screening was widely implemented in the United States in the mid-1980, we used 1985 as the surrogate year for defining pre- vs. post-mammography era in primary analyses.Participant characteristics of 488 cases and 1908 controls in the pre- and post-mammography era are presented in Table p-interaction = 0.47). When BBD subtype was further categorized into atypical ductal and lobular hyperplasia, the highest risk was observed with atypical lobular hyperplasia , followed by atypical ductal hyperplasia  in both pre- and post-mammography era (p-interaction=0.63) (Supplementary Table p-interaction=0.66) and post-mammography era (p-interaction=0.60)  and 4.24-fold (95% CI = 3.08–5.83) higher breast cancer risk, respectively, compared with non-proliferative lesions (Table p-interaction=0.11)  and the stratum of BBDs found on mammography  and the interaction was not statistically significant  women13. This observation was not confirmed in this study in either the pre- or post-mammography era.Breast cancer risks associated with BBD subtypes were reported by studies that followed up large cohorts of women undergoing breast biopsies with different baseline characteristics and indications for biopsies, possibly reducing the ability to generalize these results to women undergoing breast biopsies for abnormalities detected by screening mammography. This observation not only has potential consequences for individual patient counseling but could affect some of today’s best-known breast cancer risk prediction models that use features like the number of biopsies and BBD subtype3, whereas this study includes 488 cases and 1908 controls with biopsy-confirmed BBDs. Although the exact year that should be used for the start of widespread mammography is difficult to determine, we confirmed 77% of NHS/NHSII women aged ≥40 years received mammography in 1988/1989. A proportion of BBDs first detected on mammogram was also higher in post-mammography era (1985 and after) compared with pre-mammography era (44 vs. 9%). Further, it is generally accepted that widespread access to mammographic screening happened in the United States in the mid-1980s, and, therefore, we believe 1985 is an appropriate surrogate16. It should also be noted that we had sparse information on biopsy method and thus were not able to determine the prevalence of core needle biopsies. This fact made stratified analyses by core needle biopsy vs. surgical biopsy impossible. While such an analysis would have been informative and potentially more generalizable to contemporary practice, it was not until the late 1990s/early 2000s that core needle biopsy became the principal method for the diagnosis of non-palpable breast lesions. As the NHS and NHSII are ongoing prospective studies, it may be possible in the future to confirm our results by including more recent data from patients with image-directed core-biopsied lesions. Nevertheless, we believe this study still provides important insights since it is the first study to date that has compared the BBD–breast cancer risk associations before and after the widespread implementation of screening mammography.In this study, the use of biopsy-confirmed BBDs, the use of prospective study design, and the careful adjustment for potential confounders are important strengths. While we cannot exclude the existence of small significant differences, we were not able to detect these, given our limited sample size; if these existed, they would probably be clinically insignificant. Although sample size may be limited for stratified analyses, this study is still one of the largest studies to date that examined the BBD–breast cancer risk relationship. Our previous study published in 2007 included 395 cases and 1610 controlsIn conclusion, our data suggest that the magnitude of risk associated with BBD subtypes initially reported from women biopsied in the pre-mammography era remains valid for BBD detected after the widespread use of mammography. Given the limited information available on the type of biopsy performed, further studies of patients in which BBDs were detected by core-needle biopsy are needed to confirm our results.18. Cumulative response rates for both cohorts were >90% and were similar among women regardless of their BBD diagnosis.This study is a nested case–control study within the NHS and NHS II cohorts with biopsy-confirmed BBD. The NHS is an ongoing prospective cohort study that began in 1976, when 121,700 female registered nurses between the ages of 30 and 55 years completed a mailed questionnaire. The NHS II consists of 116,609 female registered nurses who were between the ages of 25 and 42 years when the study began in 1989. In both cohorts, participants have been followed via biennial questionnaires that provide information on lifestyle factors , family history of disease, reproductive history, and incident disease19. Briefly, cases were women with biopsy-confirmed BBD who reported a subsequent diagnosis of breast cancer following their BBD diagnosis. Cases  were diagnosed between 1976 and 1998 for the NHS and between 1989 and 1999 for the NHS II. Self-reported breast cancers were confirmed by review of medical records. To reduce potential reverse causation, women were excluded if they had evidence of in situ or invasive carcinoma at biopsy or reported a diagnosis of breast cancer within 6 months of their BBD biopsy. There was a mean of 10 years (SD = 6.93) between BBD biopsy and cancer diagnosis. Eligible controls were women who completed the questionnaire in the same year that the breast cancer case was reported and had a previous diagnosis of biopsy-confirmed BBD but were free from breast cancer at the time of the case was diagnosed . Up to four controls were selected for each breast cancer case, matched on year of birth and year of BBD biopsy. Women were excluded if they had unknown BBD lesion type. A total of 488 cases and 1908 controls, in whom the original slides had been reviewed, were eligible for this study. Due to considerable missing information on the laterality of the carcinoma in the cases, this information was not considered in the analysis. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Completion of the self-administered questionnaire was presumed to imply informed consent. This study complies with the STROBE  guidelines20.Details on the BBD diagnosis reporting on the questionnaires have been previously described21). The ability to obtain biopsy blocks did not significantly differ by case and control status. Two study pathologists independently reviewed the hematoxylin- and eosin-stained sections from the benign breast biopsy blocks and completed detailed worksheets on the subtype of BBD lesion  in a blinded manner. The details of this nested case–control study and the BBD assessment have been described previously22.Eligible cases and controls were contacted for permission to obtain their BBD pathology records and biopsy specimens, and specimens were then obtained from hospital pathology departments when possible . We considered BBDs detected on both self-exam/physical exam and mammography as first found on self-exam/physical activity . We categorized women into those who had a BBD diagnosis in the pre- vs. post-mammography era. In primary analysis, we used 1985 as the cutpoint calendar year for defining pre- vs. post-mammography era because mammography screening was widely implemented in the United States. in the mid-1980. In the sensitivity analysis, we repeated the analyses using 1980 as the cutpoint calendar year for defining mammography era. Starting in 1988 in the NHS and 1989 in the NHSII, biennial questionnaires asked questions on whether women received mammogram and the year since the last mammogram. In the NHS, 77% of women have ever had any mammogram in 1988 (with an unknown proportion for screening mammogram) and, among these women, 56% had the most recent mammogram within 1 year. In the NHSII, 77% of women at age ≥40 years have ever had any mammogram in 1989 and, among these women, 79% had the routine screening and 46% had the most recent mammogram within 1 year. In 1990–1991, 76% of NHS participants and 70% of NHSII participants had a screening mammogram.To avoid losing data due to incomplete matched sets (benign biopsy blocks were not available for some cases and controls), we performed unconditional logistic regression analysis, adjusting for matching factors, to estimate ORs and 95% CIs for the association between BBD subtype  and subsequent breast cancer risk. Multivariable models included matching factors  and potential confounders . In the secondary analysis, we further categorized proliferative lesions with atypical hyperplasia into atypical ductal hyperplasia and atypical lobular hyperplasia. To assess the variation in associations by the mode of BBD diagnosis, we stratified the analyses by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) and the methods of BBD detection (mammogram vs. self-exam/physician’s exam vs. other). In the sensitivity analysis, we repeated the analyses using 1980 as the cutpoint calendar year for mammography era. Because results could be influenced by the different length of follow-up time in the pre- vs. post-mammography era, we also excluded individuals with follow-up time >13 years (the maximum follow-up time in the post-mammography era) in the sensitivity analysis. Interaction tests were performed using the likelihood ratio test for product terms.All statistical tests were two-sided with 5% type I error. Analyses were conducted with SAS version 9 .Further information on experimental design is available in the Supplementary MaterialReporting Summary Checklist


Proper nutrition plays a major role in preventing diseases and, therefore, nutritional interventions constitute crucial strategies in the field of Public Health. Nutrigenomics and nutriproteomics are arising from the integration of nutritional, genomics and proteomics specialties in the era of postgenomics medicine. In particular, nutrigenomics and nutriproteomics focus on the interaction between nutrients and the human genome and proteome, respectively, providing insights into the role of diet in carcinogenesis. Further omics disciplines, like metabonomics, interactomics and microbiomics, are expected to provide a better understanding of nutrition and its underlying factors. These fields represent an unprecedented opportunity for the development of personalized diets in women at risk of developing breast cancer. Despite important research advancements and clinical improvements, breast cancer still represents a serious Public Health challenge, in terms of both epidemiological and economic burden . GeneticEven though common sense seems to suggest that nutritional factors can have a key role in breast tumor aetiopathogenesis and prevention, the application of methods based on rigorous approaches, such as systematic reviews and meta-analyses, has led to mixed results .It has been hypothesized that classical surveys, relying upon nutritional epidemiology tools and instruments, are plagued by errors and biases, such as inadequate nutritional assessment, population sampling or lack of a proper follow-up . FurtherNutrigenomics is emerging as a new specialty from the intersection of genomics and nutritional disciplines. It is anticipated to play a fundamental role in breast tumor prevention and early detection, in that the “identification of the relationship between nutrition and breast cancer among sporadic cases and gene mutation carriers provides necessary data for breast cancer prevention” .The purpose of the present overview is to provide an updated synthesis of the current knowledge of the effects of nutrients and diet on breast tumor, from a nutrigenomic perspective. A narrative synthesis of the major studies on the topic was undertaken, by searching in PubMed/MEDLINE. Keywords included some major nutrients, breast cancer and breast cancer-related genes.“Concerning diet, only alcohol is widely recognized for being most consistently associated with breast cancer risk. Diet seems to be modestly associated with the disease, highlighting the need for more studies to be conducted” .Adherence to a Mediterranean diet does not seem to reduce breast-cancer-related specific risk in terms of incidence rate and mortality according to a systematic review of the literature and a meta-analysis of observational studies , whilst Concerning saturated fat intake, breast-cancer-specific death (hazard-ratio or HR 1.63 (95% CI 1.19–2.24)) is higher for women consuming high amounts of fats . CholestConcerning meat, based on the findings of a meta-analysis of prospective studies, RR of breast cancer for the highest versus the lowest consumption categories resulted in 1.10 (95% CI 1.02–1.19) for red meat, and 1.08 (95% CI 1.01–1.15) for processed meat. In detail, RR was 1.11  for a daily increased uptake of 120 g of red meat, and 1.09  for a daily increased consumption of 50 g of processed meat .Regarding dairy intake, a recent meta-analysis found that a high and modest consumption  were able to reduce the risk of breast cancer compared with low dairy intake , and RR 0.94 (95% CI 0.91–0.98), respectively). The dose–response analysis showed a linear relationship between dairy consumption and breast cancer risk. In particular, subgroup analysis showed that yogurt (RR 0.91 (95% CI 0.83–0.99)) and low-fat dairy product types (RR 0.85 (95% CI 0.75–0.96)) decreased the risk of cancer, while other dairy products failed to exert such effects .Consuming five or more than five eggs weekly correlated with an increased risk of developing breast cancer (RR 1.04 (95% CI 1.01–1.07) for consuming five eggs per week and 1.09 (95% CI 1.03–1.15) for consuming around nine eggs/week) . A previProspective epidemiological investigations showed a U-shaped association between dietary folate uptake and the risk of developing breast cancer. In detail, women with a dietary folate intake ranging from 153 to 400 μg/day showed a significant reduced breast cancer risk compared with those consuming less than 153 μg/day, but not for those consuming more than 400 μg per day .When comparing the highest versus the lowest quartiles of intake, weak, non-statistically significant relationships could be reported for fruits and vegetables. No further healthy advantage emerged comparing the highest and lowest uptake deciles. No correlations could be detected for specific vegetables or fruits .Concerning some specific fruits, apple was found to exert a protective effect only in case-control studies (odds-ratio or OR 0.79 (95% CI 0.73–0.87)), but not in prospective studies . GrapefrA vegetarian diet did not confer advantages with respect to a non-vegetarian diet . HoweverThe uptake of soy, an important source of phytoestrogens and isoflavones, like daidzein  and genistein , was found to significantly correlate with a decreased risk of developing breast cancer (OR 0.78). This could be due to: (1) increased differentiation of the mammary tissue, (2) reduced bio-activation and bio-transformation from pro-carcinogens to carcinogens and (3) modulation of genes belonging to signal transduction pathways and cascades underlying tumor initiation, promotion and/or progression, such as the BRCA1/BRCA2 pathway .Ethnic factor is another parameter that could explain discrepancies in the literature. For instance, another meta-analysis showed protective effect of soy only for Asian women, both for pre- (OR 0.59 (95% CI 0.48–0.69)) and post-menopausal (OR 0.59 (95% CI 0.44–0.74)) subjects, but not for Western individuals .Concerning fish intake, a meta-analysis of prospective cohort studies found that marine n-3 polyunsaturated fatty acids assumption determined a 14% reduction in breast cancer risk ,32. AlphAlcohol uptake correlates with an increased risk of having highly dense glands  and deveAlcohol consumption after receiving a diagnosis of breast cancer did not correlate with overall survival, whereas better survival was reported in cases of pre-diagnosis consumption. Taking into account the estrogen receptor (ER) status, pre- or post-diagnosis alcohol consumption was not associated with breast-cancer-specific mortality in ER-positive breast cancer women. Moderate post-diagnosis alcohol consumption correlated with a small decrease in breast-cancer-specific mortality rate in women with ER-negative breast cancer. In conclusion, alcohol consumption after a diagnosis of breast tumor does not seem to be associated with health outcome and prognosis .Coffee uptake does not seem to be correlated with the risk of developing breast cancer , even thFinally, tea consumption has not been generally found to correlate with breast cancer risk, apart from drinking black tea, which may be associated with an increased risk . HoweverThe effects of major nutrients in terms of breast cancer risk are summarized in The previously reported discrepancies can be explained, taking into account several parameters: methodological aspects , the characteristics of the samples recruited and, above all, the molecular phenotype/endo-phenotype . In the The “Breast Cancer Type 1 susceptibility gene”  is a tumor suppressor that acts as a caretaker gene, that is to say, it is responsible for repairing DNA lesions and mutations, such as double-strand breaks, together with other oncosuppressors ,47. The As previously mentioned, inconsistency among studies assessing coffee uptake and breast cancer risk could be solved, taking into account BRCA1 mutations. Nikitina and collaborators found that, in BRCA1 mutation carriers, coffee uptake correlated with lower levels of micronuclei, demonstrating its preventive effect, potentially mediated by increased biochemical activities to sense and repair DNA damages .Utilizing a murine and an in-vitro cellular model, Donovan and colleagues  assessedKotsopoulos and collaborators  designedPirouzpanah and colleagues  assessedDziaman et al.  fond thaThe BRCA2 protein is encoded by a gene located to 13q12.3. Mutated BRCA2 can lead to a variety of disorders, including Fanconi anemia, breast, ovarian, prostate and pancreatic cancer, and malignant melanoma, among others ,62.Similar to BRCA1, genistein supplementation was found to up-regulate BRCA2 levels . Vissac-The BRCA status was found to correlate with vegetable consumption and fruit uptake (OR 0.27 (95% CI 0.10–0.80)) ,65.The “Korean Hereditary Breast Cancer Study” showed that soy intake was associated with a lower risk of breast cancer in BRCA mutation carriers . Meat intake was not associated, instead, with BRCA status .Furthermore, Bissonauth and collegues  performeCaëtano and coworkers  studied Catechol-O-methyltransferase (COMT) is an estrogen-metabolizing enzyme catalyzing the O-methylation of catechol estrogens, utilizing S-adenosylmethionine (SAM) as a source of methyls. Some of its haplotypes have been associated with an increased risk of developing breast cancer  and mammFolate, the uptake levels of which have also been demonstrated to correlate with breast cancer risk, and other micronutrients belonging to the folate metabolic pathway, can affect the concentrations of SAM and S-adenosylhomocysteine (SAH) .Among women carrying at least one low-activity COMT allele, those consuming tea displayed a significantly decreased risk of developing breast cancer (OR 0.48 (95% CI 0.29–0.77)) with respect to non-tea drinkers . The ranEpidemiological surveys have found an inverse association between vitamin D, calcium intake and mammographic breast density ,76, as wVarious VDR polymorphisms exist: Cdx-2, FokI, BsmI, ApaI, and TaqI. FokI polymorphism was related to an increased risk for breast cancer, whereas the BsmI polymorphism conferred a decreased risk ,80.2D) is involved in several biological functions, including inhibiting cell proliferation, inducing differentiation and apoptosis, and inhibiting angiogenesis in normal and breast cancer cells . Among women with high folate intake, green tea consumption was not found to be associated with breast cancer. A similar trend was reported for those women carrying the high-activity MTHFR/TYMS genotypes and frequently (weekly or daily) consuming green tea (OR 0.66 (95% CI 0.45–0.98)). This association was even stronger among women with low folate uptake but failed to achieve the significance threshold among those carrying the low-activity genotypes . Folate uptake from diet was associated with a higher breast cancer risk in women carrying the MTHFR 677CT/TT-1298AA mutation, but an inverse association was described in compound heterozygous women. A statistically significant interaction was noted between dietary folate intake and the C allele. The T allele correlated with increased breast cancer risk in women aged 55 years and older ). Homozygosis for the C allele conferred a higher risk in women aged 45–55 years (adjusted OR 1.89 (95% CI 1.09–3.29)) .A 62% increased risk of breast tumor could be observed in a sample of postmenopausal women carrying the TT genotype. Women with a higher number of variant T alleles had a higher risk of developing breast cancer. A modifying effect due to the uptake of B vitamins was described. The most relevant MTHFR-breast cancer risks were reported among women consuming low amounts of folate and vitamin B6, whereas no statistically significant increased risks could be found among women with higher uptakes .ER-α plays a major role in different steps (initiation and proliferation) of breast cancer, in that it up-regulates the expression of oncoproteins, whereas it down-regulated the levels of cell cycle inhibitors, such as P21 ,104.Dietary green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), can restore ER-α expression in an in-vitro model and can also result in a remodeling of the chromatin structure of the ER-α promoter by epigenetic changes, including altered histone acetylation and methylation status, as well as in a decreased binding of the transcription repressor complex at the level of the regulatory region of the ER-α promoter . Similar results were obtained by Donovan and collaborators , who shoMyeloperoxidase (MPO), catalase (CAT), heme oxygenase (HO) and nitric oxid synthase (NOS) encode proteins with a prominent role in the oxidative stress network. HO mediates the response to several drugs, including pharmorubicin and piperlongumine ,108,109,The study by Li and colleagues found that women consuming low amounts of fruits and vegetables and carrying low-risk alleles displayed a higher breast cancer risk. These results, taken together, seem to suggest the role of antioxidants (either endogenous or exogenous) in the process of breast tumorigenesis .The “polycomb group (PcG) protein, enhancer of zeste homologue 2” (EZH2), is over-expressed in breast tumor, and has been correlated with cancer growth, proliferation and metastasis ,114.The consumption of dietary omega-3 polyunsaturated fatty acids (PUFAs) can finely tune and modulate the levels of EZH2 in breast cancer cells. The supplementation with omega-3 PUFAs, but not omega-6 PUFAs, can result in down-regulation of EZH2, and upregulation of E-cadherin and insulin-like growth factor binding protein 3 (IGF-BP3) .Sex hormone binding globulin (SHBG) is a major biomarker of breast cancer risk, diagnosis and prognosis ,117.for trend < 0.01), and in non-Japanese Brazilian subjects carrying at least one A allele (OR for consumers versus non-consumers of 0.21 (95% CI 0.06–0.77)) [For the rs6259 SHBG polymorphism, an inverse association was found in postmenopausal Japanese women carrying the GG genotype (OR for the highest versus the lowest tertiles of 0.50 (95% CI 0.29–0.87), P6–0.77)) .“RAS-association domain family 1 isoform A” (RASSF1A) methylation is an important biomarker of breast tumor. According to a review of the literature and meta-analysis, the epigenetic modification of the gene displays a sensitivity and a specificity of 0.49 and 0.95, whilst the diagnostic odds ratio (DOR) and the area under the curve (AUC) resulted in 19.0 and 0.83, respectively .Whereas Pirouzpanah and colleagues  found a Retinoic acid receptor beta (RARB) encodes for a nuclear receptor.Pirouzpanah and collaborators  found th“Glutathione S-transferase P type 1” (GSTP1), an enzyme encoded by the GSTP1 gene, is responsible for the xenobiotic metabolism ,122. RecLee and collaborators  recruiteThe main findings of the interactions between gene polymorphisms and nutrients and their effects in terms of breast cancer risk are summarized in Breast cancer imposes a tremendous burden in terms of epidemiological, societal implications and economic costs. The association between breast cancer and diet is complex, multi-factorial and non-linear. Classical nutritional epidemiological surveys have demonstrated conflicting results, showing a modest correlation between diet and breast cancer risk . We can speculate that this may be due to the complexity of breast cancer, which is a multi-faceted, highly heterogeneous disorder. Histological and, recently, molecular classifications have contributed to underpin a rather complex picture.Therefore, we need molecular details: we need nutrigenetics and nutrigenomics. Nutrigenomics and allied disciplines can foster advancements in knowledge in this field, shedding light on the molecular background of breast cancer tumorigenesis, and paving the way towards personalized treatments ,126,127.


Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer  with only one ER-negative case, Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.The online version contains supplementary material available at 10.1186/s13058-021-01410-1. It is well established that benign breast diseases (BBDs) increase the risk of breast cancer in women . In the Since women diagnosed with BBD comprise a large proportion of future breast cancer cases ~ 30%), it is important to identify factors associated with subsequent BC 0%, it is. Within Breast cancer is a heterogeneous disease, with data strongly supporting different associations of risk factors such as parity and genetic susceptibility loci by tumor subtypes defined by hormone receptor status and other clinical/pathologic features –12. WhetN = 15,395; age range 21–85 years); one control had a BBD diagnosis in 2012. Invasive breast cancer diagnoses were obtained through record linkage with the KPNW Tumor Registry, as previously described [We utilized data from a previously designed case-control study of BBD and breast cancer risk , nested escribed . BrieflyWe obtained information on the following variables from the KPNW Tumor Registry: date of invasive breast cancer diagnosis, date of death, tumor histology and behavior using ICD-O coding, grade, AJCC clinical staging variable, tumor size, and lymph node status. Immunohistochemistry (IHC) data on key markers were obtained for ER (which has been measured on cases since the mid-1970s), PR (first measured in 1983), and HER2 status (first measured in 1988). The percentage of tumors analyzed for ER status increased from 0% in 1980 to 18% in 1989, 54% in 1994, and 85% in 2006; HER2 status was available on 43% of tumors until 2001 and on 68% from 2002 onward.Risk factor data were captured using routine medical records, which include information on clinic visits, prescriptions, operations, and laboratory testing. These data were linked using the KPNW unique health record numbers to identify each individual member. From these records, data were available for various exposures. We focused on established or suspected breast cancer risk factors, specifically family history of breast cancer, age at menarche, parity, age at first birth, body mass index (BMI) at benign biopsy, menopausal status, and menopausal hormone use. KPNW has a well-characterized mammography screening program, and by 1993, more than 75% of women over 45 had had a screening mammogram . For thiBBD histology was assessed according to the Page classification criteria , as follhttps://www.src.isr.umich.edu/software/iveware-documentation/iveware-with-sas/). Details of imputation steps are delineated in a flow chart  was seen for the age at menarche variable see . We did % was seeP ≤ 0.05 was considered statistically significant and all tests were two-sided. All analyses were performed using SAS V9.4.Descriptive statistics of demographic and tumor characteristics by calendar year of BBD diagnosis and age at breast cancer diagnosis were assessed using chi-squared or Fisher’s exact tests. Conditional logistic regression and unconditional logistic models adjusted for the matching factors yielded similar estimates , well or moderately differentiated (73.6%), ER-positive (85.9%), PR-positive (71.2%), HER2-negative (79.4%), lymph node-negative (73.6%), and of ductal histology (83.5%). The invasive cases were overwhelmingly of low stage, with < 10% of cases being diagnosed as stage III or IV. As expected, ER status differed significantly by age at breast cancer diagnosis, with a higher proportion (24.5%) of ER-negative breast cancers diagnosed among women ≤ 50 compared to those older than 50 (12.8%). We also assessed whether there were differences in tumor characteristics by calendar period before and during/after 1993 . Of the Association results for all cases combined for established risk factors, including BBD characteristics, are shown in Supplemental Table P-heterogeneity = 0.24). Compared with patients with non-proliferative BBD, those with proliferative BBD with atypia had a greater than fivefold increased risk for ER-positive disease . There was only one ER-negative case; hence, too few cases to provide a reliable estimate in this subgroup. After accounting for BBD histology, the presence of CCLs at BBD diagnosis was associated with a 1.5-fold increased risk for both ER-positive (95% CI = 1.03–2.29) and ER-negative (95% CI = 0.73–3.07) tumors (P-heterogeneity = 0.94).Risk associations by ER status for patient characteristics and histologic features of BBD are presented in Table P-het = 0.054. Associations for patient and histologic characteristics by tumor size  are presented in Supplemental Table P < 0.0001) and presence of CCLs (P = 0.038) with increased breast cancer risk were somewhat stronger among patients with smaller tumors.While breast cancer risk associations for patient and histologic characteristics were generally consistent by tumor grade, we found suggestive evidence that higher levels of involution were inversely associated with reduced risk among well-differentiated tumors  = 0.51 , Supplemental Table P-het = 0.09.We performed additional analyses stratified by menopausal status using factors that have been significantly associated with breast cancer risk, in our study population Table . The assWe did not find evidence of heterogeneity in risk factor associations before and after 1993 when 75% of women over 45 had had a screening mammogram  are precursor lesions for breast cancer , 31, eviReduced lobular involution has been previously shown to be a significant factor associated with elevated breast cancer risk among women with BBD , 43, 44.This is a unique cohort of women enrolled in a general community healthcare plan, providing the population access to screening and preventative services that may not be typical for other subsets of the US population. It is not currently known whether women with BBD are followed and screened more closely compared to women without BBD diagnoses. Current data from a study of over 42,000 screened women in Spain found that women with a previous benign breast disease diagnosis had a higher cumulative risk of screen-detected cancer and interval cancers, consistent with data supporting BBD as a risk factor for breast cancer regardless of the mode of detection . WhetherA limitation of our study is that risk estimates are based on a BBD patient population diagnosed on excisional biopsies during a calendar period spanning the adoption of widespread mammography screening, which became more commonplace in KPNW around 1993; thus, associations may not be reflective of BBD diagnosed in more recent years. Since 1995, advances in breast imaging technologies have resulted in a shift in diagnostic biopsy procedures to core needle biopsies, which currently comprise about 80% of biopsies in the USA . Based oWithin this BBD cohort, the largest to date with longitudinal follow-up, we provide breast cancer risk factor associations within an HMO patient population . Our datAdditional file 1: Supplemental methods. Supplementary Figure 1. Steps of multiple imputation . Supplemental Table 2. Comparison of associations between select patient characteristics and histologic features with breast cancer risk in conditional and unconditional logistic regression models using multiple imputation dataset (N = 1028). Supplemental Table 3. Associations between select patient characteristics and histologic features with breast cancer risk by tumor grade (N = 922). Supplemental Table 4. Associations between select patient characteristics and histologic features with breast cancer risk by tumor size (N = 1013). Supplementary Table 5. Associations between demographic and histologic features with breast cancer risk by BBD calendar year before vs. after 1993 (N = 1028). Appendix A. Distribution of numeric variables before (top) and after (bottom) multiple imputations.


Diabetes is one of the most important chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. Several types of research have been conducted to ascertain the link between diabetes and its potential for increasing the risk of breast cancer. This research aims to determine the relationship between diabetes and breast cancer; patients with diabetes have a higher risk than the general population of developing cancer, and diabetes patients have a higher incidence and mortality of breast cancer. This research also reviewed the relationship between cytokines, the mitogenic effect of insulin-like growth factors, and breast cells. The review includes searching the PubMed database using the keywords “diabetes,” “breast cancer,” “risk factor,” and “premenopausal.” The search returned 53 articles used for review of this article.  Diabetes is a medical disease that causes an increase in blood glucose levels. A fasting blood glucose of 126 mg/dL or higher or an oral glucose tolerance test of 200 mg/dL or higher confirms diabetes. The symptoms of diabetes include increase urinating, feeling very thirsty, feeling hungry, and extreme fatigue. Other symptoms include blurry vision, cuts and bruises that are slow to heal, weight loss despite increased food consumption (type 1), and tingling, pain, or numbness in the hands and feet (type 2). All the symptoms of diabetes result from high glucose levels in the blood, affecting different cells, tissues, and organs [Cancer is a medical condition that results from the excessive proliferation of unhealthy tissue. This proliferation of cells can be well differentiated  or less similar  compared to the cell of origin or no function. The characteristic of cancers is their ability to invade and destroy surrounding tissues and cells; this also includes metastasis. There are different types of cancer affecting a different part of the body or organs varying in severity, prognosis, and mortality. Cancers are abnormal cells that grow out of control ignoring signals to stop dividing or programmed cell death .Breast cancer is caused by malignant cells (cancerous cells) that proliferate excessively in the breast and invade the surrounding tissue or cells and can spread to another area of the body (metastasis). This type of cancer occurs mostly in women and can affect any location in the breast . Cancer The research reviews articles from the PubMed database using the keywords “breast cancer,” generating 406,997 hits, then the keywords “breast cancer” and “diabetes,” which resulted in 4,827 hits. The research was further narrowed to “breast cancer,” “diabetes,” and “risk factors” in “premenopausal women” generating 53 articles. Based on the articles used from the database and keyword searches, there is an association between diabetes and breast cancer. Type 2 diabetes is a medical disease that affects more than 7% of adults in developed countries, and up to 10% to 20% of patients with breast cancer have diabetes; the significant risk factors for type 2 diabetes are old age and obesity, which are also risk factors for breast cancer . StudiesA meta-analysis was undertaken using a random-effects model to investigate the association between diabetes and breast cancer risk and the risk of breast cancer in women with type 2 diabetes was increased by 27%, although the risk was decreased by 16% after adjustment for body mass index (BMI) . According to Wolf et al., “three mechanisms have been postulated to associate diabetes with breast cancer: activation of the insulin pathway, activation of the insulin-like growth factor pathway, and regulation of endogenous sex hormones” . AnotherIGF-1 is a mitogenic agent to breast cells, and in the circulation, this mitogen binds with IGF-binding protein 3 (IGFBP-3). Premenopausal women showed increased IGF-1 serum concentrations, decreased IGFBP-3 levels, and increased IGF-1/IGFBP-3 ratios. This IGF-1/IGFBP-3 ratio is essential in determining breast cancer risk coupled with other factors, such as age, hormonal use, and family history . This paSimilar to IGF-1, insulin is also a mitogen and plays a significant role in breast cancer, and this might be related to underlying insulin resistance . The expOverproduction of insulin-like growth factor receptor  and mutations in genes encoding these enzymes are in several types of cancer such as colon, breast, and prostate cancers. IGFR overproduction and mutation have become targets for new therapeutic interventions . Type 2 Insulin resistance and reduced estrogen production result in a complex metabolic disorder that contributes to the development of cancer in organs with high estrogen demand including breast, endometrium, and ovaries. Insulin resistance leads to a compensatory mechanism that increases the production of androgens and decreases the production of estrogen . InsulinTumors linked to diabetes may secrete cytokines, especially those that secrete large amounts of interleukin-6, which is associated with insulin resistance and inflammatory signaling throughout the body . In estrOne of the strongest risk factors for breast cancer is high breast cancer density; along with other factors, insulin treatment associated with mammographic density does not imply increased breast cancer risk . Other bThe relationship between diabetes and breast cancer was confirmed by most studies with large patient populations . The assDiabetes can lead to end-organ damage and indirectly affects breast cancer by influencing screening and treatment choices, affecting treatment toxicities, and potentially leading to a worse outcome in breast cancer patients. Lifestyle modifications such as weight loss increased physical activity, and dietary changes are attainable in breast cancer populations. Individuals who make lifestyle changes after a breast cancer diagnosis experience several physical and psychological benefits . In breaThere is a slight increase in the risk of developing breast cancer among women with type 2 diabetes. A decreased level of estrogen as a result of insulin resistance increases the risk of developing cancer in any organ with high levels of estrogen receptors, including breast, endometrium, and ovaries. This review highlights the different mechanisms by which cytokines, IGF-1, and IGFBP-3 levels increase the risk of developing breast cancer. Awareness of these relationships enables healthcare providers to explore ways to support enhanced screening and lifestyle changes to minimize the mitogenic effects of insulin-like growth factors.


Background: Evidence remains inconsistent regarding the potential influence of β-blocker (BB) use on clinical outcomes in women with breast cancer. We aimed to evaluate the association between BB and prognosis of breast cancer in an updated meta-analysis.Methods: Follow-up studies comparing the clinical outcomes of breast cancer in women with and without use of BB were included by search of PubMed, Embase, and Cochrane’s Library. A random-effect model was used to pool the results.Results: Seventeen observational studies were included. Pooled results did not support a significant association between BB use and breast cancer recurrence , breast cancer related deaths , or all-cause deaths  in women with breast cancer. Study characteristics such as sample size, definition of BB use, follow-up durations, adjustment of menopausal status, or quality score did not significantly affect the results. Subgroup analyses showed that BB may be associated with a trend of reduced risk of all-cause deaths in women with breast cancer in prospective studies , but not in retrospective studies .Conclusions: Current evidence from observational studies does not support a significant association between BB use and improved prognosis in women with breast cancer. Breast cancer is one of the most common malignancies in women . CurrentThe MOOSE   and CochElectronic databases of PubMed, Embase, and the Cochrane’s Library were systematically searched using the combination of the following terms: (1) “adrenergic beta antagonist” OR “beta blockers” OR “beta antagonist” OR “beta adrenoreceptor antagonist” OR “beta adrenergic receptor antagonist” OR “beta adrenergic blocking agent” OR “adrenergic beta-1 receptor antagonists” OR “acebutolol” OR “alprenolol” OR “atenolol” OR “betaxolol” OR “bisoprolol” OR “bunolol” OR “bupranolol” OR “Bucindolol” OR “carteolol” OR “celiprolol” OR “Carvedilol” OR “dihydroalprenolol” OR “esmolol” OR “iodocyanopindolol” OR “labetalol” OR “levobunolol” OR “metipranolol” OR “metoprolol” OR “nadolol” OR “Nebivolol” OR “oxprenolol” OR “penbutolol” OR “practolol” OR “pindolol” OR “propranolol” OR “sotalol” OR “timolol”; (2) “breast cancer”; and (3) “survival” OR “prognosis” OR “mortality” OR “death” OR “recurrence” OR ”surgery" OR “operation”. The search was limited to human studies without restriction of the publication language. The reference lists of original and review articles were also analyzed manually. The final literature search was performed on December 24, 2019.Studies were included if they met the following criteria: (1) published as full-length article; (2) designed as follow-up studies, including randomized controlled trials (RCTs), cohort studies, nested case–control studies, and post-hoc analyses of RCTs, with a minimal follow-up duration of one year; (3) included women with breast cancer; (4) compared the clinical prognosis between breast cancer women of users and non-users of BB; (5) documented the incidence of at least one of the outcomes during follow-up, including breast cancer recurrence, breast cancer related deaths and all-cause deaths; and (6) reported the adjusted risk ratios  and their corresponding 95% confidence intervals (CIs) for the above outcomes in users and non-users of BB. Reviews, editorials, preclinical studies, cross-sectional studies, and conference abstracts were excluded.Literature search, data extraction, and study quality assessment were independently performed by two authors according to the predefined inclusion criteria. If inconsistencies occurred, discussion with the corresponding author was suggested to resolve these issues. The following data were extracted: (1) name of the first author, publication year, study location, and study design; (2) characteristics and numbers of women with breast cancer, mean ages, definition of BB use, and follow-up period; and (3) number of cases with breast cancer recurrence, breast cancer related deaths, and all-cause deaths during follow-up, and variables adjusted when presenting the RRs. The quality of observational study was evaluated using the Newcastle–Ottawa Scale (NOS) . This scQ test was performed to evaluate the heterogeneity among the include cohort studies [I2 statistic was also calculated. A significant heterogeneity was considered if I2 > 50%. A random-effect model was used to pool the results since this model has been indicated to incorporate the potential heterogeneity of the included studies and therefore could provide a more generalized result. Sensitivity analysis by omitting one study at a time was performed to evaluate the stability of the results [The association between BB use and breast cancer recurrence or mortality outcome was measured by RRs in the present study. To stabilize its variance and normalized the distribution, RR data and its corresponding stand error (SE) from each study was logarithmically transformed . The Coc studies ,36, and  results . Predefi results . Potenti results . The RevThe flowchart of database search was shown in Overall, this meta-analysis included 17 studies  with 75,P for Cochrane’s Q test < 0.001, I2=77%). Pooled results with a random-effect model showed that the association between BB use and breast cancer recurrence was not significant . Subgroup analysis indicated that the association between BB use and breast cancer recurrence was not significantly affected by study characteristics including study design, sample size, definition of BB use, follow-up durations, adjustment of menopausal status, or NOS . Subgroup analysis indicated that study characteristics such as study design, sample size, definition of BB use, follow-up durations, adjustment of menopausal status, or NOS did not significantly affect the results . Subgroup analysis indicated that study design may affect the outcome. Specifically, BB may be associated with a trend of reduced risk of all-cause deaths in women with breast cancer in prospective studies , but not in retrospective studies .The funnel plots for the association between BB and risks of recurrence, breast cancer related deaths, all-cause deaths in In the present study, by pooling the results of available observational studies, we found that the BB use is not associated with significantly affected breast cancer recurrence, breast cancer related deaths, or all-cause deaths. Sensitivity analyses by omitting one study at a time did not significantly change the results, demonstrating that the results are stable. Subgroup analyses showed that characteristics such as sample size, definition of BB use, follow-up durations, adjustment of menopausal status, or quality score did not seem to significantly affect the results. Moreover, BB may be associated with a trend of reduced risk of all-cause deaths in women with breast cancer in prospective studies, but not in retrospective studies. Taken together, this updated meta-analysis showed that current evidence from observational studies does not support a significant association between BB use and improved prognosis in women with breast cancer. However, in view of the potential anticancer effects of BB evidenced in experimental studies and the potential limitations of the retrospective studies, qualified RCTs are needed to eventually determine if BB has additional clinical benefits in women with breast cancer.Previous meta-analyses showed inconsistent results regarding the association between BB use and prognosis in women with breast cancer. An early meta-analysis with seven studies published before 2015 showed that BB was associated with a significantly reduced risk of breast cancer related deaths, but not for cancer recurrence or total mortality . Howeverin vitro through inhibition of the reactive oxygen species-mediated phosphoinositide 3–kinase/protein kinase B pathway [In contrast with the non-significant association between BB use and breast cancer prognosis as evidenced by the observational studies, experimental studies and small-scale RCTs consistently showed potential beneficial effects of BB in breast cancer. A recent study showed that Carvedilol treatment could suppress malignant proliferation of mammary epithelial cells  pathway . Moreove pathway . Interes pathway . These f pathway ,44. ThesOur study has limitations that should be noticed when interpreting the results. First, although data of adjusted RR were combined, residual factors may also exist that may confound the association between BB and prognosis of breast cancer, such as concurrent use of other medications that may affect the prognosis of breast cancer, such as metformin  and statIn conclusion, our meta-analysis showed that current evidence from observational studies did not support a significant association between BB use and improved prognosis in women with breast cancer. Considering the limitations of observational studies, qualified RCTs are needed to eventually determine if BB has additional clinical benefits in women with breast cancer.


BRCA1 and BRCA2 mutations and MBC has been well-established; recent data suggest that CHEK2 1100delC heterozygosity is also associated with an increased risk of MBC. Herein, we present the case of a 47-year-old male who was initially diagnosed with bilateral symmetric gynecomastia on a diagnostic mammogram performed for right breast palpable lump. Sixteen months after his diagnosis of gynecomastia, he presented with enlarging right breast palpable lumps and underwent a diagnostic mammogram and breast ultrasound. Ultrasound-guided biopsies were performed on the right breast mass and axillary lymphadenopathy. Pathology revealed right breast invasive ductal carcinoma (IDC) and right axillary metastatic lymphadenopathy. Subsequent genetic testing found CHEK2*1100delC mutation. This case report focuses on the presentation, diagnosis, and management of breast cancer, as well as long-term cancer screening in the setting of CHEK2 mutation in a relatively young male patient.Male breast cancer (MBC) is a rare disease that accounts for less than one percent of all breast cancers. The association between  BRCA 1 and BRCA2 mutations. In addition, CHEK2 mutations have been shown to predispose both women and men to specific types of breast cancer. CHEK2 protein is a cell-cycle checkpoint kinase, responsible for phosphorylating the tumor suppressor proteins p53 and BRCA1, which subsequently leads to either cell cycle arrest or activation of DNA repair proteins. Loss-of-function variants in CHEK2 are known to be pathogenic as they result in impaired DNA repair and genomic instability. More specifically, the 1100delC variant results in the deletion of one nucleotide from exon 11 of the CHEK2 mRNA, causing a frameshift at codon 367; this forms a premature stop codon, creating a disrupted or absent protein product and abolishing the kinase function of CHEK2 [CHEK2 mutation is inherited in an autosomal dominant manner [Male breast cancer (MBC) is a rare occurrence, comprising less than 1% of cancer in men and less than 0.2% of all cancer-related mortality among men. Risk factors for the development of breast cancer in men include alcohol use, as well as factors that could lead to a hyperestrogenic state, such as obesity, cirrhosis, testicular injury, and undescended testes [CHEK2 mutation and female breast cancer has been extensively studied in the past. According to one meta-analysis by Weischer et al., CHEK2 1100delC variant can increase the risk of breast cancer three- to five-fold among women; in addition, women with a family history of breast cancer are estimated to have a 37% cumulative risk of breast cancer at age 70 years, while those with no family history of breast cancer are estimated to have a 21% cumulative risk [et al. confirmed the significant association between the CHEK2 1100delC variant and female breast cancer risk, particularly in familial breast cancer cases among Caucasians [The association between ive risk . Anotherucasians .CHEK2 mutation has also been associated with an increased risk of MBC, although the association has not been as well-studied as in female breast cancer [CHEK2 mutation and MBC thus far, however, one can conclude that the prevalence of CHEK2 mutation is higher in some countries compared to the others. Higher rates of CHEK2 mutation have been reported in studies from Northern European countries, mainly the Netherlands; the mutation, however, seems to be rare in Australia, Spain, and Ashkenazi Jews [CHEK2 mutation.t cancer . From thazi Jews . Therefoazi Jews . Herein,2. His social history is positive for a 45-pack-year history of cigarette smoking, which he has now quit, as well as heavy alcohol abuse until one year ago, which he has recently cut down to one shot of whiskey a day. Sixteen months after his diagnosis of gynecomastia, the patient presented with a two-month history of right retroareolar palpable mass along with new-onset tingling, numbness, and pain of the right breast. On exam, the patient had a right-sided subareolar mass measuring 5 x 3 cm that was mobile from chest wall but fixed to skin, along with color changes of the nipple. In addition, he had a right axillary mass that was mobile and approximately 3 cm in size. A diagnostic mammogram and breast ultrasound showed an irregular right retroareolar mass along with an abnormal-appearing right axillary lymph node, both of which were highly suggestive of malignancy (BI-RADS 5)  regimen with curative intent, followed by evaluation for post-mastectomy radiation therapy by radiation oncology and at least five years of endocrine therapy with Tamoxifen.In addition, given that he is a male with breast cancer, he was recommended to undergo genetic counseling, as he met the National Comprehensive Cancer Network (NCCN) criteria for hereditary cancer testing . The patCHEK2 mutation, sixteen months after he was found to have bilateral symmetric gynecomastia on a mammogram. The peak age for MBC is 71 years old, while our patient is only 47 years old. Although our patient has gynecomastia, which is found in 6% to 38% of males affected by breast cancer, gynecomastia per se is not a risk factor of MBC [CHEK2 mutation; the combination of all these risk factors could have led to a relatively early onset of breast cancer in this patient.Our case presented a 47-year-old male who was diagnosed with right-sided invasive ductal carcinoma in the setting of r of MBC . The risMale patients presenting with breast symptoms such as breast enlargement, nipple discharge, breast pain, and palpable lump are usually concerned about the underlying cause and whether or not the symptoms are a manifestation of breast cancer. The most common cause of breast symptoms in male patients is gynecomastia, especially in younger patients, as MBC has a later onset on average in comparison to gynecomastia, which can present at any age . DetectiCHEK2 mutation and MBC. According to a study by Wasielewski et al., CHEK2 1100delC is associated with an increased risk for MBC particularly in the Dutch population, with the average age at diagnosis of 69 years; most of the CHEK2 1100delC MBC cases in the study were also ER/PR positive compared to CHEK2 1100delC negative cases [et al. investigated the link between CHEK2 mutation and ER status in women with early-onset breast cancer and found a four-fold increased risk of ER-positive breast cancer, suggesting that Tamoxifen could be used as chemoprevention in the setting of confirmed CHEK2 mutation [Although not as extensively studied as in female breast cancer, recent studies have explored the link between mutation .et al., breast tumor characteristics of CHEK2 mutation carriers do not differ from those of non-carriers, with no significant differences observed in terms of tumor morphology, angioinvasion, or lymph node involvement [CHEK2 carriers as non-carriers. Due to the rarity of MBC, recommendations regarding its management is based upon the results of clinical trials focusing on female breast cancer. Surgery is usually the first step in the treatment of MBC. Modified radical mastectomy is generally preferred over radical or total mastectomy due to a lower rate of complications despite no significant difference in cancer recurrence or survival. Breast-conserving surgery (lumpectomy) is another option but is usually not feasible due to the central location of most male breast tumors, as well as the small breast volume in men. Another important part of the surgical treatment of invasive MBC is axillary lymph node dissection [According to a study by Marjanka olvement . Therefossection . In addissection . Adjuvanssection . In termssection . Adjuvanssection . The samssection . Our patCHEK2 mutation can predispose to other types of cancer. According to a study by Näslund-Koch et al., CHEK2 heterozygosity is associated with a 15-82% increased risk for any cancer; they propose that this mutation could be a susceptibility allele for any cancer, especially given its function as a protein kinase involved in DNA repair and stability [et al. suggests that second primary cancers, such as cancers of colon, thyroid, lung, and kidney, are more frequent in CHEK2 mutation carriers compared to non-carriers [et al. and another by Xiang et al., have explored the link between the CHEK2 mutation and colorectal cancer and have found an increased risk for colorectal cancer among CHEK2 mutation carriers [In addition to breast cancer, tability . Anothercarriers . In addicarriers ,19. For carriers . Our patCHEK2 mutation is inherited in an autosomal dominant fashion, our patient was informed that other family members may also carry this pathogenic variant. He was informed that children of CHEK2 carriers also have a 50% risk to carry the pathogenic variant with a 50% chance for his son to carry the familial CHEK2 pathogenic variant. Since it is unclear whether the CHEK2 pathogenic variant was maternally or paternally inherited at this point, testing his maternal and paternal relatives can help determine which family members are also at risk of carrying the pathogenic variant. The patient was encouraged to discuss the results with his family members and to talk to them regarding seeking genetic counseling to clarify their risk.Moreover, since CHEK2 mutation explains his diagnosis of MBC at a relatively younger age. The patient also has gynecomastia, but gynecomastia is not a risk factor for breast cancer according to the current literature. Breast cancer genetic testing is important after diagnosis of MBC to provide further information to the patient as well as his family members. Due to the association of CHEK2 mutation with other malignancies, further cancer surveillance is recommended for patients with this mutation.In most cases, when a male presents with a breast lump, the diagnosis will be gynecomastia. However, MBC is also on the differential, and thus, assessment with a diagnostic mammogram and breast ultrasound can be helpful. MBC is uncommon, and it typically occurs in elderly men with a peak age of 71 years old. In this case, the patient is only 47 years old. Although he is relatively younger than the peak age for MBC, his genetic predisposition with the


Mammographic breast density (MBD) is an important imaging biomarker of breast cancer risk, but it has been suggested that increased MBD is not a genuine finding once corrected for age and body mass index (BMI). This study examined the association of various factors, including both residing in and working in the urban setting, with MBD. Questionnaires were completed by 1144 women attending for mammography at the London Breast Institute in 2012–2013. Breast density was assessed with an automated volumetric breast density measurement system (Volpara) and compared with subjective radiologist assessment. Multivariable linear regression was used to model the relationship between MBD and residence in the urban setting as well as working in the urban setting, adjusting for both age and BMI and other menstrual, reproductive, and lifestyle factors. Urban residence was significantly associated with an increasing percent of MBD, but this association became non-significant when adjusted for age and BMI. This was not the case for women who were both residents in the urban setting and still working. Our results suggest that the association between urban women and increased MBD can be partially explained by their lower BMI, but for women still working, there appear to be other contributing factors. Mammographic breast density (MBD) has been recognized as an independent biomarker of breast cancer risk, with risk prediction of relevance to both primary and secondary prevention ,2. In thMBD is influenced significantly by age and body mass index (BMI) ,6 and thThe aim of this study was to investigate the associations of various factors, including BMI, age, lifestyle, menstrual, and reproductive factors, as well as place of work and residence  with MBD and to compare the association of these factors with percent breast density and absolute volume of dense tissue. An additional aim was to compare MBD measurements obtained with an automated observer-independent quantitative breast density measurement system with qualitative MBD assessment by subjective radiologist review.This prospective study was carried out at The London Breast Institute at the Princess Grace Hospital, an independent hospital providing specialist breast care services, including screening and diagnostic mammography. The study was reviewed by the Hospital Corporation of America (HCA) Healthcare UK Research Review Committee on behalf of the Princess Grace Hospital and was considered to be audit, not research, and therefore did not require specific ethics committee approval.The study population consisted of 1144 women attending for full-field digital mammography (GE 2000D) at the London Breast Institute between late October 2012 and January 2013 and consenting to participate in this study. These represented approximately 85% of the total number of women attending for mammography during this period. Women were given a questionnaire at the time of attendance, together with a letter explaining the purpose of the study, and if willing to participate, they could complete the questionnaire at that time or return it later by post. It was made clear in the letter that women were welcome to discuss any further questions at the time with the technologist performing the mammogram. Completion of the questionnaire was therefore taken as consent to participate. Approximately half of the women were asymptomatic and attending for routine screening mammography, while the rest were symptomatic, with various complaints ranging from pain to the presence of a breast lump.The questionnaire included items on demographic information, lifestyle factors, menstrual and reproductive variables, and use of hormone replacement therapy (HRT) or oral contraceptives (OCs). Questions on past history of breast biopsy, cancer diagnosis, and family history of breast cancer were also included, together with information on the postcode of residence at the time of the most recent mammogram, previous postcode if the woman had moved within the past 5 years, postcode of place of work, and postcode of the previous place of work if this had changed within 5 years.n = 56), information was taken from the patient records. Working in the urban setting was defined on the basis of the current place of work, excluding those with work type recorded as “homemaker” or “retired”, who would not be travelling to work.These postcodes were used to determine whether or not the woman was a resident and/or worked in the urban setting, i.e., London. Where the postcode of the place of residence was missing from the questionnaire . Percent breast density, absolute density (the absolute amount of fibroglandular volume), and total breast volume for each woman were calculated as averages for all views for the given attendance/study date. Automated percent density measurements were allocated by Volpara software into Volpara Density Grades (VDGs): VDG 1 = 0.0–4.4% density, VDG 2 = 4.5–7.4%, VDG 3 = 7.5–15.4%, VDG 4 > 15.4%, these grades being equivalent to radiologist visually allocated BI-RADS density grades . Non-denTwo experienced specialist breast radiologists (NP and KP) also performed subjective visual estimation of the content of fibroglandular dense tissue within the breast, which was recorded according to the fourth edition BI-RADS Atlas as A = almost entirely fatty, B = scattered fibroglandular densities, C = heterogeneously dense, or D = extremely dense  Figure .p = 0.2, and with age, and BMI, and either residence or working in the urban setting always included. Multivariable regression analyses were also carried out separately for postmenopausal and pre/peri-menopausal women. p-values < 0.05 were considered statistically significant.Percent and absolute breast density measurements were both log-transformed. Analyses of percent density were also adjusted for total breast volume, and the analyses of absolute density adjusted for non-dense volume. Separate multivariable regression analyses were carried out: (1) Including urban residence, (2) including working in the urban setting for those women currently working, and (3) including both urban residence and working in the urban setting. Because of the amount and pattern of missing variables, and also because of co-linearity between variables, we conducted forward stepwise regression in multivariable regression analyses, but with a generous inclusion criterion of Of the 1144 women, 1105 had at least one mammography attendance for which automated volumetric breast density data were available; from these, 99 women reporting previous breast cancer and a further 39 women for whom BMI could not be calculated were excluded, leaving a total of 967 included in the analysis.3 (SD 7.1), and average percent volumetric density was 4.2% (SD 3.9). For women aged 55 years of more, the corresponding figures were 9.6 cm3 (SD 6.0) and 2.5% (SD 3.1). Increasing age was negatively correlated with both percent and absolute breast density, both alone and adjusted for BMI. Increasing BMI was negatively correlated with percent breast density but positively correlated with absolute breast density . For womA total of 62.2% (602/967) of women were urban residents; only a further 25 women had previously been urban residents in London. Of the 378 women with data on the current place of work, 282 (74.6%) worked in the urban setting; only a further 6 had worked in the urban setting in the past 5 years. Of the 282 women working in the urban setting, 103 (36.5%) reported walking to work, 106 (37.6%) taking the London Underground, 60 (21.3%) taking the overground train, 104 (36.9%) travelling by car, and 56 (19.9%) travelling by bus; some women reported more than one method of transport.p = 0.01) as well as in women working in the urban setting compared with those working elsewhere .Mean BMI was significantly lower in women who were urban residents compared with those who were not  when analyzed alone, but this association became non-significant when BMI and age were included in the multivariable model (p = 0.45). In the multivariable model, increasing BMI (p ≤ 0.001), increasing age (p ≤ 0.001), and being postmenopausal (p ≤ 0.001) were significantly associated with lower percent breast density, whereas current HRT use (p = 0.01) and increased age at menarche (p = 0.01) were significantly associated with higher percent breast density. Detailed results for the multiple regression analysis including urban residence are shown in Urban residence in London was significantly associated with higher percent breast density , ever having breast fed (p = 0.04), and having fewer than five drinks per week (p = 0.002) were significantly associated with lower absolute breast density, whereas increasing BMI (p = 0.003) and current HRT use (p = 0.01) were significantly associated with higher absolute breast density.In the analysis for absolute breast density, there was no significant association between urban residence and absolute breast density. Being postmenopausal (p = 0.07), either alone or when BMI and age were included (p = 0.45). Detailed results for the multiple regression analyses including working in the urban setting are shown in p ≤ 0.001), increasing age (p ≤ 0.001), and being postmenopausal (p = 0.03) were significantly associated with lower percent breast density, while increased age at menarche (p = 0.04) was significantly associated with higher percent breast density.Working in the urban setting was not associated with percent breast density , and hysterectomy (p = 0.02) were significantly associated with higher absolute breast density. Analyses of postmenopausal and pre/perimenopausal women showed similar results.In the analysis for absolute density, working in the urban setting was also not associated with absolute density. Increasing BMI was not significantly associated with lower absolute breast density, whereas parity (p = 0.002). For those living in London and still working there, the average percent breast density was 13.1 , whereas for those living outside of London and/or not working there, the average was 11.3 . This remained the case if the variable for working in the urban setting was excluded and the data was restricted to those women currently working. This was also the case in pre/perimenopausal women.In the multivariable regression analysis including the significant factors in p < 0.001).Percent breast density as measured by automated systems was considerably less than that estimated visually by radiologists. The correlation coefficient of the quantitatively measured VDG groupings with the subjective visual estimation according to BI-RADS was 0.80  with increased MBD ,12. HoweCurrent use of HRT has been shown in other studies to be associated with increased MBD, but a negative association with OC use has been less widely reported. We found no association with use of anti-estrogens, although the numbers reporting such use were small. Our finding that ever having breast fed was negatively associated with increased absolute MBD is consistent with the results of others, and indeed the decreased MBD associated with earlier menarche has also been observed elsewhere ,22.The results of our study highlight the importance of adjustment for age and BMI in analyses of MBD as a risk factor for breast cancer. They also contribute to the debate on whether percent or absolute density is more relevant but were not sufficient to draw firm conclusions. A study in young women at intermediate familial risk found that absolute, but not percent, MBD was a significant risk factor for breast cancer after adjusting for the area of non-dense tissue  and thatApart from factors, including BMI, age, lifestyle, menstrual, and reproductive factors, and urban vs. rural place of work and residence, there is variation as to whether the percent breast density or absolute volume of dense tissue is the most accurate predictive measure of breast cancer risk . MoreoveThe limitations of this study include the reliance on questionnaire data, with the potential for recall bias. Urban residence or working was determined based on the relevant postcodes; however, this was a fairly broad classification, and may not reflect differences between small geographical areas.In conclusion, urban women in our study population had a lower BMI and our results confirm an association between residential environment and MBD. We found no association between living or working in an urban environment and increased MBD once we adequately accounted for the confounding influence of BMI and age. However, there is a possible genuine association of increased MBD in women living in an urban environment and currently working. The reasons for this are unclear but may be related to lifestyle factors or increased exposure to pollution, particularly the different air quality found between urban and rural areas, which may have a weak yet cumulative estrogenic effect ,15,16,25