Breast cancer risk associated with allele variant genes in the estrogen pathway

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Lifetime estrogen exposure is a known risk factor for breast cancer. Several risk factors that are thought to reflect a women’s lifetime exposure to estrogen, such as early menarche, late menopause, late age at first full-term pregnancy, high body mass index, and low parity, have been linked to breast cancer. While the main effect of estrogen is thought to be the induction of mitogenesis in breast epithelial cells that leads to clonal expansion of altered cells, there is growing evidence that estrogen metabolites also initiate DNA mutations. We examined the relationship between allele variant genes in the estrogen metabolism and signal transduction pathways and breast cancer in a case-control study of the greater Baltimore-area. The frequency distribution of several polymorphisms were studied in 279 breast cancer cases and 279 age- and race-matched controls collected from 1992-2002. DNA was extracted from blood and tissue samples and genotyped with Taqman-based assays. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression and were adjusted for age, race, menopausal status, and family history. Three polymorphisms, two in cytochrome P450 17A1 (CYP17A1) and one in estrogen receptor alpha (ESR1), were found to be associated with breast cancer. A homozygous wild type to homozygous mutant C-to-T change at codon 46 (His46) of CYP17A1 was found to be associated with a 2.6-fold increased risk (95% CI, 1.3-5.0; p-value = 0.005). There was a significant linear trend with a p-value of 0.01. In addition, a homozygous wild type to homozygous mutant T-to-C change at -34 of CYP17A1 was also found to be associated with a 3.5-fold increased risk (95% CI, 1.7-7.0; p-value = 0.001) There was a significant linear trend with a p-value of 0.01. For ESR1, the homozygous wild type to homozygous mutant G-to-A change at codon 594 (Thr594) was associated with a 4-fold lower risk (OR, 0.19; 95% CI, 0.1-0.6; p-value = 0.004). There was a significant linear trend with a p-value of 0.01. Our observations support the hypothesis that genetic polymorphisms in the estrogen pathway modify human breast cancer risk. We are currently studying more genotypes in this pathway and will also investigate, in genotyped primary human breast epithelial cells from reduction surgery, how these polymorphisms affect the estrogen-signaling pathway.