Abstract
Abstract Although estrogens have long been implicated in the etiology of breast cancer, the mechanisms through which estrogens contribute to breast cancer development remain poorly defined. Furthermore many of the genes that influence the risk of developing breast cancer also remain to be determined. The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is being used to elucidate the mechanisms through which estrogens contribute to breast cancer development and to identify novel genetic determinants of breast cancer susceptibility. Female ACI rats develop mammary cancer at an incidence nearing 100% when treated with physiological levels of E2. In contrast, both the Brown Norway (BN) and Copenhagen (COP) rat strains are resistant to E2-induced mammary cancer. A total of nine quantitative trait loci (QTL), designated Emca1 (Estrogen-induced mammary cancer) through Emca9, have been mapped in a series of intercrosses between ACI and COP rats (Emca1-2) or ACI and BN rats (Emca3-9). The purpose of the current study is to fine map the Emca1 and Emca8 genetic determinants of mammary cancer susceptibility, which were mapped to rat chromosome 5 (RNO5). ACI alleles at these QTL act to increase the number of mammary cancers per rat and to decrease the latency to the appearance of the first palpable mammary cancer. A series of congenic rat strains have been generated by introgressing defined segments of RNO5 from the resistant COP or BN rat strains onto the genetic background of the susceptible ACI strain. By defining the susceptibility of these congenic rat strains relative to that of the parental ACI strain, Emca8 has now been localized to an approximate 10 megabase (Mb) region of distal RNO5. Similar studies are underway to determine whether or not Emca1 maps to the same region of RNO5 as Emca8. As currently defined, Emca8 harbors approximately 200 known and predicted genes as well as a copy number variant (CNV) that differs between the ACI, COP and BN rat strains based on array comparative genomic hybridization (aCGH). To help identify the mechanisms through which Emca1 and Emca8 determine susceptibility to mammary cancer, we have defined gene expression profiles for normal mammary gland from E2 treated ACI, COP and BN rats and identified those genes that reside within Emca1 and Emca8 and are differentially expressed between ACI and COP or BN rats. Gene expression profiles were also defined for mammary cancers induced by E2 in ACI rats to identify those genes that reside within these QTL and are differentially expressed between normal and neoplastic mammary tissues. The mapping and expression data that define the genomic architecture of Emca1 and Emca8 will be presented and discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2011-2387
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