Abstract
IntroductionThe female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy.MethodsWe conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).ResultsThe strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT = 0.002; overall PACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.ConclusionsWe found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT.
Highlights
The female sex steroids estrogen and progesterone are important in breast cancer etiology
Tagging single-nucleotide polymorphism (SNP) selection and genotyping We investigated 24 genes that are involved in female sex steroid hormone biosynthesis, metabolism, or excretion
Imputation We imputed SNPs in gene regions where we found a statistically significant association (P < 0.01 before multiple testing correction) with breast cancer risk among all women or among subgroups defined by menopausal status
Summary
The female sex steroids estrogen and progesterone are important in breast cancer etiology. Reproductive and hormonal factors, including age at menarche, parity, number of full-term pregnancies, age at first full-term pregnancy, breastfeeding, age at menopause, body mass index (BMI), and physical activity, are associated with breast cancer risk [1,2]. Consistent with these observations, breast cancer risk is higher among women with higher circulating levels of endogenous estrogen [3,4,5] and among women using combined postmenopausal estrogen and progestin therapy (EPT) [6,7,8,9,10,11]. It is possible that the inconsistencies may be explained at least partly by differences in the distribution of environmental factors that modify the effects of genetic polymorphisms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
