Download or read book An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk written by and published by . This book was released on 2008 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: CHT use has been demonstrated to confer an increased risk of breast cancer. Genetic variation in hormonal pathways may modify the effect of CHT on breast cancer risk. Using 1237 cases and 1015 controls from two population-based case-control studies of breast cancer, we investigated the effect of genetic variation in 7 genes within the progesterone pathway using a tagSNP and functional SNP approach and 5 genes within the catechol estrogen pathway. Within single gene analyses we observed breast cancer risk to be modestly associated with one SNPs in each GSTP1 (rs1695: OR = 1.4 [95% CI: 1.02-1.9] for carriers of A allele); CYP1B1 (rs1056827: OR = 1.7]95% CI:1.2-2.5] for T homozygotes); SRD5A1 (rs248793: OR=1.2 [95% CI: 1.02-1.5] for G homozygotes) and PGR (rs492457: OR=1.5 [95% CI: 1.01-2.1] for carriers of the A allele). We found that the breast cancer risk associated with SNPs was particularly strong in long-term CHT users. In a multi-gene model including two genes with single gene effects within the estrogen pathway (CYP1B1*2 and GSTP1), breast cancer risk was 1.6 (95% CI: 1.03-2.4) times higher for carriers of 1 high risk genotype and 2.8 (95% CI: 1.5-5.3) times higher for women with 2 high risk genotypes compared to women with 0 high risk genotypes. The impact of high risk genotypes was stronger in long-term CHT users, particularly in long-term, current CHT users (OR=5.6 [95% CI: 1-5-20.6]). These results suggest that breast cancer risk among CHT users is modified by variation in genes within hormonal pathways.

Download or read book Pregnancy Related Characteristics Genetic Variation in Estrogen Metabolizing Enzymes and Maternal Risk of Breast Cancer written by David Jaworowicz Jr and published by . This book was released on 2011 with total page 244 pages. Available in PDF, EPUB and Kindle. Book excerpt: ABSTRACTConsiderable evidence has accrued from in vitro, clinical, and epidemiologic studies indicating that cumulative lifetime exposure to elevated levels of circulating ovarian hormones, including estrogens and progesterone, is a significant contributing factor in breast carcinogenesis. Pregnancy represents a crucial time period that substantially impacts a woman's lifetime risk of breast cancer, with younger age at first pregnancy and multiparity conferring a protective effect on long-term risk. The exact mechanisms by which pregnancy may reduce risk have been the focus of widespread research, with considerable emphasis on the contribution of hormonal influences. Particular maternal experiences or complications in pregnancy may be indicative of altered hormonal profiles. These pregnancy-related characteristics could potentially serve as proxies for distinct hormone exposures, and provide insight into the role that estrogens may have on breast cancer risk.^The goal of this doctoral dissertation project was to investigate and characterize the association between breast cancer risk and five pregnancy-related characteristics, including pregnancy-induced hypertension, preeclampsia or eclampsia/toxemia, gestational diabetes, pregnancy-associated weight gain, and pregnancy-related nausea and vomiting (NV). Given that these pregnancy-related characteristics are suspected to reflect distinct hormone profiles during and perhaps beyond pregnancy, including marked differences in estrogen exposures, we also examined genetic variation in key estrogen-metabolizing enzymes in relation to these characteristics to determine if genotype modified breast cancer risk. We evaluated a total of seven single-nucleotide polymorphisms in five genes coding for the following enzymes: cytochrome P450s CYP17, CYP1A1, and CYP1B1; catechol-O-methyltransferase; and glutathione-S-transferase P1.^Overall, a total of 2,918 women with at least one reported pregnancy were included in these analyses (1,001 cases with primary, incident, histologically-confirmed breast cancer and 1,917 controls frequency matched by age and race). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models, adjusting for suspected confounders. Pregnancy-related nausea and vomiting during any pregnancy was associated with a statistically significant reduction in breast cancer risk in premenopausal (OR 0.61; 95% CI 0.42-0.90) and postmenopausal (OR 0.73; 95% CI 0.58-0.92) women. Significant and consistent inverse associations were observed with greater percentage of pregnancies in which nausea and vomiting occurred, increased NV severity, and NV lasting longer into pregnancy. These associations did not differ by estrogen receptor (ER), combined ER and progesterone receptor (ER/PR), or human epidermal growth factor receptor 2 (HER2) expression status.^No significant associations with breast cancer risk were found for any of the other pregnancy-related characteristics. Carriers of the rare allele for the functional CYP1B1 rs1056836 SNP, a genotype which codes for enhanced enzyme activity, exhibited marginally positive associations with the likelihood of NV experience during pregnancy compared to common homozygous genotypes (OR1.22, 95% CI: 0.98-1.52 for the GG/GC compared to CC genotype). Significant multiplicative interactions between pregnancy-associated NV and this genotype in relation to breast cancer risk were found in both premenopausal and postmenopausal populations.^While null or slightly elevated risks were observed with NV among women with the common homozygous CC genotype, statistically significant reductions in breast cancer risk were observed for those with genotypes containing the rare G allele (OR 0.54, 95% CI: 0.32-0.91 [p for interaction = 0.036] in premenopausal women and OR 0.57, 95% CI: 0.41-0.78 [p for interaction = 0.011] in postmenopausal women). The findings presented herein suggest that nausea and vomiting during pregnancy may be associated with a reduction in breast cancer risk. Although there is no evidence of independent associations between estrogen-metabolizing enzyme genotypes and breast cancer risk, there may be associations between CYP1B1 polymorphisms and NV. Effect modification by CYP1B1 rs1056836 genotype on the association between NV and breast cancer risk provides evidence of a possible mechanistic role for estrogen or its metabolites.

Download or read book The Controversy over Hormone Replacement Therapy Evaluating Related Risk of Breast Cancer and Other Diseases written by and published by Am Cncl on Science, Health. This book was released on with total page 18 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Hormones and Breast Cancer in Post Menopausal Women written by Sandra Z. Haslam and published by IOS Press. This book was released on 2006 with total page 128 pages. Available in PDF, EPUB and Kindle. Book excerpt: Focuses on the challenges of determining the mechanistic basis for the role of hormones in the etiology of postmenopausal breast cancer. This book intends to bring attention to the advancements and challenges facing effective prevention and treatment of this disease.

Download or read book Cancer and the Environment written by Institute of Medicine and published by National Academies Press. This book was released on 2002-08-01 with total page 160 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Roundtable on Environmental Health Sciences, Research, and Medicine wanted to address the link between environmental factors and the development of cancer in light of recent advances in genomics. They asked what research tools are needed, how new scientific information can be applied in a timely manner to reduce the burden of cancer, and how this can be flexible enough to treat the individual.

Download or read book Hormone Replacement Therapy and Breast Cancer written by Linda L. Humphrey and published by . This book was released on 2002 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: OBJECTIVE: To evaluate and update the prior review evaluating the risk of breast cancer and breast cancer (BCA) death associated with the use of postmenopausal hormone replacement therapy (HRT) by reviewing the medical literature which has been published since the last US Preventive Services Task Force update. DATA SOURCE: All English language studies identified in the Medline database from 1992-2000 and all previously published meta-analyses. In addition, reference lists of key articles, letters, and editorials were reviewed for all related studies, including those pre-dating the database search. STUDY SELECTION: All studies that evaluated breast cancer incidence or mortality as a primary or secondary outcome in association with hormone replacement therapy published between 1992-2000. Studies evaluating the effect of hormone replacement therapy on breast density were also reviewed. DATA EXTRACTION: The following studies met inclusion criteria: 8 meta-analyses from the years 1988-1997, 1 nested case-control study, 14 case-control studies, and 15 cohort studies all evaluating breast cancer incidence, mortality, or both. Of the 15 cohort studies, 10 represented unique cohorts and of the 14 case control studies, 2 involved updates of the same case set. Data from each study were abstracted to prepared forms. When more than one study from the same population was reported, data from the most recent publication were reviewed. If data from the same population were analyzed by cohort and by case-control analysis, both results were reported if they evaluated different outcomes. In addition, several studies evaluating breast density and HRT were reviewed, and the best studies summarized. DATA SYNTHESIS: For ever or short-term use of estrogen, 7 of the 8 meta-analyses, 8 of the 11 case-control studies, and 6 of the 7 cohort studies evaluating incidence showed no increase in breast cancer with hormone replacement therapy. Of the original studies reviewed evaluating incidence, 12 of 19 showed no increased risk of breast cancer with long duration ERT or HRT use. However, 5 of the meta-analyses showed increased risk with duration over 5 years and 2 important cohort studies showed increased risk with longer duration use. Eleven original studies evaluated combined estrogen and progestin, and one showed increased risk of BCA with short-term use; 3 of the 5 evaluating duration with combined therapy showed increased risk that was statistically significant. Current use of ERT was associated with significantly increased risk of breast cancer in two of the best cohort studies; use of combined therapy was associated with increased risk in 3 studies. Six recent cohort studies (1992-2000) evaluated breast cancer mortality in association with hormone use: 1 showed increased risk of death, 4 showed decreased risk of death, and one showed no association. Several recent studies show that post-menopausal estrogen therapy is associated with increased breast density by mammography and that adding progesterone to estrogen results in even greater increases in breast density. Finally, there is evidence suggesting an important interaction between HRT and alcohol use and HRT and lower body weight. CONCLUSIONS: The association of short-term hormone replacement therapy with the development of breast cancer is uncertain based on multiple studies with inconsistent findings. Among studies indicating increased risk, the risk is largely confined to current and long-term use (>5-10 years), and the risk is relatively small (RR 1.2-1.5). Reduced mortality is a fairly consistent finding among the studies evaluating breast cancer mortality and HRT use. The addition of progesterone to estrogen and current, as well as long-term, use may be associated with breast cancer risk above that of estrogen itself. Although the biological plausibility of an association between postmenopausal hormone use and breast cancer is high, the studies showing risk or benefit from the use of post-menopausal hormones are limited by the observational nature of the epidemiologic data existing to date. Data from randomized controlled trials are needed to validly evaluate the relationship.

Download or read book A Family History of Breast Cancer written by Dawn Marie Grabrick and published by . This book was released on 2001 with total page 416 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The Molecular Actions of Medroxyprogesterone Acetate on Androgen Receptor Signalling and the Promotion of Breast Cancer written by Aleksandra Monica Ochnik and published by . This book was released on 2012 with total page 828 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Women's Health Initiative (WHI) clinical trial was the first randomised, double blind, placebo-controlled disease prevention trial to demonstrate epidemiological evidence of a casual link between the use of combined hormone replacement therapy (cHRT) comprising conjugated equine estrogens (CEE) and the synthetic progestin medroxyprogesterone acetate (MPA) and increased breast cancer risk in post-menopausal women. Since the first WHI report in 2002, other observational studies have demonstrated that it is the addition of the synthetic progestin in the cHRT that is associated with an increase in breast cancer risk. The focus of this thesis was to investigate the following hypothesis formulated in the Dame Roma Mitchell Cancer Research Laboratory, which proposed that MPA possesses antagonistic actions on androgen receptor (AR)-signalling and thereby can disrupt the protective effect of androgens in the breast, thus leading to an increased risk of breast cancer. Androgens have been associated with a growth restrictive role in breast tissue in both humans and animals and are now emerging as key hormonal pathways involved in the pathogenesis of breast cancer. The objectives of this thesis were firstly to determine the relationship between the use of cHRT containing MPA and breast cancer incidence in Australian women, and secondly to perform biological studies to investigate the effect of AR-action in breast epithelial cells. Initial findings described in this thesis led to the identification of a positive association between the use of cHRT preparations containing MPA and breast cancer incidence in Australian women. Subsequent biological based studies were undertaken with non-malignant breast tissues samples from pre- and post- menopausal women in an ex vivo breast explant tissue culture experimental model and the oestrogen receptor (ER), progesterone receptor (PR) and AR positive ZR-75-1 breast cancer cell line to investigate the actions of MPA on AR-signalling and cancer-related intracellular signalling pathways. Collectively these studies demonstrated that the actions of MPA can impede the anti-proliferative actions of DHT in both human postmenopausal non-malignant and malignant breast epithelial cells via AR-mediated actions. Furthermore, the combined actions of DHT and MPA were also shown to de-regulate cancer-related intracellular pathways compared to individual hormone treatments. The findings described in this thesis provide novel results indicating that MPA may promote the development of breast cancer in post-menopausal women taking cHRT via AR-mediated actions and that use of this form of hormone therapy remains a major public health concern.

Download or read book Hormone Replacement Therapy and Breast Cancer written by U. S. Department of Health and Human Services and published by CreateSpace. This book was released on 2013-06-28 with total page 132 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this systematic evidence review, we evaluate data on the relationship between the use of postmenopausal hormone replacement therapy (HRT) and the risk of breast cancer (BCA). The context of this review is in the overall evaluation of postmenopausal hormone replacement therapy as chemoprophylaxis for chronic conditions. The results from this report will be used as part of an overall report on the risks and benefits of hormone replacement therapy for postmenopausal women. Hormone replacement therapy is used in the United States and worldwide to treat symptoms of menopause and to prevent chronic conditions such as osteoporosis. It is one of the most commonly prescribed drugs in the U.S.; a recent survey in the U.S. of postmenopausal women ages 50 to 75 showed that nearly 38% of women were currently using estrogen or hormone replacement therapy (58.7% of those with prior hysterectomy and 19.6% without hysterectomy). A major and as yet unanswered clinical question is whether hormone replacement therapy increases a woman's risk of breast cancer. This issue is a critical one because the use of HRT is prevalent and because breast cancer is a relatively common disease, so that even a small increase in breast cancer in association with hormone use could significantly influence public health. The importance of endogenous estrogen in the development of breast cancer has been evaluated and confirmed in multiple studies of differing methodologies. Studies in animals have shown that breast cancer can be induced by the administration of estrogen. Among humans, some studies have shown that women with increased levels of circulating estrogen are at higher risk for the subsequent development of breast cancer. Other studies have had conflicting findings, and some have shown this relationship in postmenopausal women only. Reproductive events are important risk factors for breast cancer. Those shown to increase risk include early menarche and late menopause, both of which prolong exposure to higher levels of estrogen as well as other reproductive hormones. Other reproductive experiences, such as late age at first pregnancy and nulliparity, increase breast cancer risk. Oopherectomy among premenopausal women is protective against breast cancer, possibly because of reduced exposure to estrogen. Other risk factors also suggest an important role for estrogen in BCA development. In postmenopausal women, obesity, which correlates with increased estrogen levels, is also associated with an increased risk of BCA. Recent studies have also shown that increased bone density, possibly a reflection of lifetime estrogen exposure, is associated with increased rates of breast cancer. Finally, age-adjusted rates of increase in breast cancer incidence slow at menopause when estrogen levels fall. There are several critical key questions to consider when evaluating the research describing the role of exogenous estrogen or estrogen/progesterone in breast cancer development and prognosis. First, is either estrogen alone or estrogen with progesterone associated with a change in breast cancer mortality? Second, does short-term estrogen use increase the risk of breast cancer? The third question, which is most relevant to the use of estrogen to prevent chronic conditions, is whether long-term estrogen increases breast cancer risk. The fourth question, which reflects the current standard of practice, is whether the combination of estrogen and progesterone, either short-term or long-term, increases the risk of breast cancer. Fifth, is current use of estrogen or hormone replacement therapy associated with increased risk of breast cancer? Sixth, are there subpopulations of women who might be at increased risk of breast cancer when using HRT? Finally, because increased breast mammographic density is independently associated with an increase in breast cancer risk, as well as with decreased accuracy of mammography, does estrogen or estrogen/progestins change breast density?

Download or read book Investigation of Genetic Polymorphisms in the Progesterone and Estrogen Pathways as Modifiers of the Effect of Hormone Therapy on Breast Cancer written by Kerryn W. Reding and published by . This book was released on 2008 with total page 216 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Stress and Breast Cancer written by Cary L. Cooper and published by . This book was released on 1988 with total page 238 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years interest has increased in the links between stress and breast cancer, reflecting the growing concern at the continuing increase in the disease. This book brings together leading researchers in the field to review the evidence available.

Download or read book Hormones Genes and Cancer written by Brian E. Henderson and published by Oxford University Press, USA. This book was released on 2003 with total page 450 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hormonal carcinogenesis is an important and controversial area of current research. In addition to accelerating existing cancers, can hormones play the role of primary carcinogens? How do genetic factors influence hormone-related cancer risk? Hormones, Genes, and Cancer addresses these questions. Over the past few decades, cancer research has focused on external environmental causes(e.g., tobacco smoke, viruses, asbestos). With the advent of new genetic sequencing techniques, we are just now beginning to understand how the body's internal environment(i.e., the hormones and growth factors that determine normal development) influences cancer etiology and prevention. From molecular insights to clinical analyses, this volume provides state-of-the-art information on the complex interactions between hormones and genes and cancer. The epidemiology and molecular endocrinology of prostate, breast, uterine, ovarian and testicular cancer are detailed in this timely treatise.

Download or read book Analysis of Cancer Risks in Populations Near Nuclear Facilities written by National Research Council and published by National Academies Press. This book was released on 2012-06-29 with total page 424 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the late 1980s, the National Cancer Institute initiated an investigation of cancer risks in populations near 52 commercial nuclear power plants and 10 Department of Energy nuclear facilities (including research and nuclear weapons production facilities and one reprocessing plant) in the United States. The results of the NCI investigation were used a primary resource for communicating with the public about the cancer risks near the nuclear facilities. However, this study is now over 20 years old. The U.S. Nuclear Regulatory Commission requested that the National Academy of Sciences provide an updated assessment of cancer risks in populations near USNRC-licensed nuclear facilities that utilize or process uranium for the production of electricity. Analysis of Cancer Risks in Populations near Nuclear Facilities: Phase 1 focuses on identifying scientifically sound approaches for carrying out an assessment of cancer risks associated with living near a nuclear facility, judgments about the strengths and weaknesses of various statistical power, ability to assess potential confounding factors, possible biases, and required effort. The results from this Phase 1 study will be used to inform the design of cancer risk assessment, which will be carried out in Phase 2. This report is beneficial for the general public, communities near nuclear facilities, stakeholders, healthcare providers, policy makers, state and local officials, community leaders, and the media.

Download or read book The Genetics of Sex Hormones and Their Effects on Mammographic Density in Women written by Cameron B. Haas and published by . This book was released on 2021 with total page 82 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this work we leveraged genomic information from large-scale population-based studies to explore the relationships between three epidemiologic factors associated with breast cancer in women: 1) mammographic density, 2) sex hormone concentrations, and 3) body mass index (BMI). Mammographic density, which describes the proportion of dense (i.e., epithelial and stromal) tissue in the breast, is one of the strongest predictors of breast cancer in women. Women with extremely dense breasts have a 3 to 6-fold increased risk of breast cancer compared to those with primarily fatty breasts. Breast cancer is generally considered to be a primarily hormone-driven cancer, an attribute that has led to the development of effective treatment and prophylactic strategies for hormone receptor positive subtypes and cause for investigating the role of endogenous hormones in breast cancer etiology. Finally, BMI has been consistently observed to have paradoxical associations with breast cancer across menopause, with evidence of preventative effects associated with higher BMI in premenopausal women but increased risk in postmenopausal women. We first built on recent analyses that investigated the genetic architecture of testosterone and sex hormone binding globulin (SHBG) in men and women of European ancestry by conducting genome-wide association studies (GWAS) of estradiol concentrations in women. Additionally, we investigated the generalizability of previous findings in women of African ancestry. We further conducted menopausal status specific GWAS of these sex hormones to identify loci with heterogeneous effects across menopause. We found that the strongest overall genetic predictor of testosterone concentrations, located in the CYP3A7 gene, had an effect nearly twice as large in premenopausal women compared to postmenopausal women. Similarly, genetic variants in the AKR1C4 gene were strongly associated with concentrations of SHBG in premenopausal women, but not in postmenopausal women, with a 5-fold difference in effect estimates between the two. We also estimated the shared heritability across menopausal status specific hormone concentrations, and observed a relatively low genetic correlation between pre- and postmenopausal detectable levels of estradiol, whereas comparisons of pre- and postmenopausal shared heritability for SHBG and testosterone were both close to one, indicating near identical genetic architectures. We performed gene-level tests for enrichment of genetic associations within tissue-specific gene expressions by collapsing multiple SNP-level associations in a gene while accounting for linkage disequilibrium. Using this gene-set analysis for tissue specificity we observed a change from strong adrenal gland tissue specificity of testosterone in premenopausal to adipose tissue specificity in postmenopausal women, suggesting that adiposity may play a more important role in determining circulating concentrations of testosterone after menopause. To understand the directional relationships between overall and menopausal status specific concentrations of sex hormones and BMI on mammographic dense and non-dense area we performed Mendelian Randomization analyses. We created menopausal status specific genetic instruments for SHBG, testosterone, and estradiol based on our previous work. We obtained single nucleotide polymorphisms (SNP)-specific association statistics from a recent GWAS of mammographic density of up to 27,900 women of European ancestry. Effect estimates for BMI were obtained from the largest meta-GWAS of BMI to date, comprising more than 700,000 individuals. We observed an inverse relationship between overall genetically predicted testosterone and dense area. Increasing genetically predicted BMI was strongly associated with an increase in genetically predicted non-dense area, as previously observed. However, we also observed an inverse association between genetically predicted BMI and absolute dense area, which might explain some of the reduced risk of breast cancer associated with an increase in genetically predicted BMI. Higher genetically predicted BMI was also strongly associated with decreasing SHBG concentrations, as well as increasing concentrations of testosterone. Based on the inverse-variance weighted results, we observed increasing genetically predicted BMI to be associated with a decrease in genetically predicted detectable levels of overall and premenopausal specific estradiol concentrations, but not for postmenopausal only. Multivariable MR approaches for the association of BMI and mammographic density adjusting for sex hormones did not substantively change the effect estimates of BMI. Building on the strong association between BMI and mammographic density, we sought to identify genetic loci that interact with BMI to alter mammographic density phenotypes. We conducted genome-wide tests for the interaction between SNPs and BMI on percent mammographic density, absolute dense area, and absolute non-dense area in 14,837 women. Despite having the largest sample size to date with genetic and phenotypic data for mammographic density, we did not find any loci that reached standard Bonferroni correction for statistical significance. This work presents novel findings of the unique genetic architectures of menopausal specific concentrations of sex hormones in women and extends these findings to investigate their associations with mammographic density. We show that BMI plays an important role in determining not only non-dense area, but also dense area and a possibly separate mechanism for breast cancer etiology. Additionally, there is evidence based on our MR approaches of a regulatory role of BMI on endogenous estradiol as yet another possible pathway to tumorigenesis. We did not identify any genetic variant that has a strong modifying effect of BMI on mammographic density phenotypes. It is possible that larger studies are merited to investigate the interactions between germline genetic variants and BMI on mammographic density variation.

Download or read book Genetic Causes of Breast Cancer and Treatments written by Elia V. Acosta and published by . This book was released on 1997 with total page 40 pages. Available in PDF, EPUB and Kindle. Book excerpt: This study investigates the genetic, hormonal, and possibly dietary factors that contribute towards breast cancer. The grouping of some families reveals a genetic predisposition involving tumor suppressor genes.

Download or read book Hormones and Breast Cancer written by Malcolm C. Pike and published by . This book was released on 1981 with total page 520 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Oxidative Stress Genetic Polymorphisms and Breast Cancer Risk written by Sylvia K. Quick and published by . This book was released on 2008 with total page 85 pages. Available in PDF, EPUB and Kindle. Book excerpt: Oxidative stress is believed to play an important role in the development and progression of breast cancer. Three central enzymes in oxidative stress pathways are manganese superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPX1). For each enzyme, a single functional genetic polymorphism was selected and the genotypes determined for women in the Western New York Exposures and Breast Cancer study, a population-based case-control study. Cases (n=1170) were women with primary, incident, pathologically confirmed postmenopausal breast cancer. Randomly selected controls (n=2115) were frequency matched to cases on age and race. Extensive information was collected on potential confounders and effect modifiers, such as diet, alcohol use and hormone use. Genotypes were assayed by MALDI-TOF. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounders. A single genotype alone was not associated with breast cancer risk for any of the three genes. GPX1 TT genotype was associated with an increased risk of breast cancer among those who also had the SOD2 CC genotype (OR 2.15, 95% CI 1.07-4.34). We stratified on several lifestyle factors; SOD2 genotype was associated with breast cancer risk among premenopausal women with low BMI. The association of CAT genotype with risk among postmenopausal women differed by level of alcohol consumption, with increased risk associated with CT/TT genotype among women reporting higher alcohol consumption. The associations of both CAT and GPX1 with postmenopausal breast cancer risk depended upon use of hormone replacement therapy. The relationship between CAT genotype, hormone replacement therapy and breast cancer risk was investigated in detail. Ever use of hormone replacement therapy was associated with an increase in risk (OR 1.39, 95% CI 1.11-1.75). The increased risk associated with ever use was more pronounced among those with the variant CT or TT CAT genotypes (OR 1.88, 95% CI 1.29-2.75) than among those with the common CC genotype (OR 1.15, 95% CI 0.86-1.54). Similarly, risk associated with five or more years of HRT use was greater among those with at least one variant T allele (OR 2.32, 95% CI 1.50-3.59). Increased risk was restricted to estrogen receptor positive breast cancer. Our findings suggest that, while none of the three genotypes significantly impact breast cancer risk when considered in isolation, simultaneous consideration of genotype of oxidative stress genes and environmental exposure revealed that genotype may be a significant breast cancer risk factor for certain subgroups of women. This observation provides insight into the etiology of breast cancer, suggesting that oxidative stress plays a role in breast carcinogenesis.