Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (z10 years versus never; odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P trend = 0.0002). Statistically significant interactions between CYP1A1 Ile

BACKGROUNDBreast cancer (BC) is a complex disease, and the incidence rates for BC increase with age. Both environmental factors and genetics have an impact on the risk of BC. Although the effects of environmental factors may vary with age, it has been assumed generally that the penetrance of single nucleotide polymorphisms (SNPs) is constant throughout life. In the current study, the results demonstrated that certain SNPs exhibit BC risk associations that vary considerably with age.METHODSSNPs in 12 steroid hormone pathway genes were investigated for associations with BC risk in white women who were enrolled in an age‐matched, case‐control (1:2 for cases and controls, respectively) study that consisted of a discovery set (n = 5000 women) and an independent validation set (n = 1583 women).RESULTSSignificant age‐related trends were identified and confirmed for SNPs in 4 genes associated with BC risk. The cytosine/cytosine (C/C) genotype of cytochrome P450 XIB2 (CYP11B2) was associated with decreased risk at younger ages (ages 30–44 years) but an increased risk at older ages (ages 55–69 years). The homozygous cytosine‐guanine (CG/CG) genotype of uridine phosphorylase glycosyltransferase 1A7 (UGT1A7) was associated with increased risk at younger ages but decreased risk at older ages. Associations in cytochrome P450 19 (CYP19) and progesterone receptor (PGR) were confined to middle age (ages 45–54 years).CONCLUSIONSThe identification of age‐specific genetic associations may have profound implications for future etiologic studies of BC and for the use of SNP genotyping to accurately predict the risk of BC in women. Cancer 2007. © 2007 American Cancer Society.

Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene-gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5-5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.

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The prohibitin 3' untranslated region (3'UTR) belongs to a novel class of non-coding regulatory RNAs. It arrests cell cycle progression by blocking G1-S transition in breast and other cancers. Our previous studies comparing MCF7 derived clones constitutively expressing a common allelic form of prohibitin RNA (UTR/C) to various controls demonstrated that it functions as a tumor suppressor. Here, we further characterized the morphology and motility of these transgenic breast cancer cells when grown in cell culture and on nude mice. In contrast to empty vector (EV) cells, UTR/C cells were observed to grow in an organized manner with more cell-cell contact and differentiate into structures with a duct-like appearance. Computer assisted cytometry to evaluate differences in nuclear morphology was performed on UTR/C and EV tissues from nude mice. Receiver operator curve areas generated using a logistic regression model were 0.8, indicating the ability to quantitatively distinguish UTR/C from EV tissues. Keratinocyte growth factor-induced motility experiments showed that migration of UTR/C cells was significantly reduced (80-90%) compared to EV cells. Together, these data indicate that this novel 3'UTR influences not only the tumorigenic phenotype but also may play a role in differentiation and migration of breast cancer cells.