Abstract 2856: Genetic variations in the hormone pathway genes and breast cancer risk in the California Teachers Study

Abstract

Abstract Background: It is well established that the female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in biosynthesis and metabolism of these hormones may affect breast cancer risk. However, the results from genetic epidemiological studies investigating the role of variation in such genes so far have been mixed. We selected 27 genes in the estrogen and progesterone synthesis and metabolism pathway and investigated whether variation in these genes was associated with breast cancer risk. Methods: We analyzed data from a breast cancer case-control study nested in the California Teachers Study. We genotyped 365 tagging single nucleotide polymorphisms (SNPs) in 27 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age and geographic area. We calculated P values adjusted for multiple correlated tests (PACT) within a gene. Results: The most significant associations were observed for several SNPs in SLCO1B1, a solute carrier organic anion transporter gene. SLCO1B1 is important in estrogen metabolism as it transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into the hepatocytes. Among the 38 tagging SNPs of SLCO1B1, 9 SNPs were associated with breast cancer risk with the smallest p-value (P=0.005) for rs11045773. Several SNPs in HSD17B4 (rs382719 and rs17388769) and HSD17B3 (rs394243), both involved in hormone metabolism, also showed associations with breast cancer risk, but these were not statistically significant after correcting for multiple testing. When we examined the associations separately by menopausal status, 10 SNPs in SLCO1B1 showed significant associations with postmenopausal breast cancer risk, and 5 of them (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene. The smallest P value among postmenopausal women was obtained for rs11045777, with OR=0.77 (95% CI=0.65-0.90, P=0.0009, PACT=0.019). Among premenopausal women, rs17388769 in HSD17B4 was associated with breast cancer risk (OR=1.56, 95% CI=1.15-2.13, P=0.004, PACT=0.051). Polymorphisms in other hormone pathway genes tested in this study were not associated with breast cancer risk in pre- or postmenopausal women. Furthermore, after additional Bonferroni adjustment for the number of genes tested, none of the genetic associations presented here were statistically significant. Conclusions: We found some evidence that genetic variation in SLCO1B1 is associated with breast cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2856.