Abstract 1393: Fine mapping and characterization of Emca8.2, a genetic determinant of susceptibility to estrogen-induced mammary cancer on chromosome 5 in the rat.

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, the Brown Norway (BN) rat strain is resistant to E2-induced mammary cancer. A total of seven quantitative trait loci (QTL), designated Emca3 (Estrogen-induced mammary cancer) through Emca9, have been mapped in reciprocal intercrosses between ACI and BN rats. The purpose of the current study is to fine map the Emca8 genetic determinants of mammary cancer susceptibility, which was mapped to rat chromosome 5 (RNO5). ACI alleles at this 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 BN rat strain 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, a locus determining susceptibility to E2-induced mammary cancer, designated Emca8.2, has now been localized to a 1.1 megabase (Mb) region of distal RNO5 containing approximately 1200 genetic sequence variants. To help identify the mechanisms through which Emca8.2 determines susceptibility to mammary cancer, the expression levels of the candidate genes within the fine-mapped region have been investigated. The mapping and expression data that define the genomic architecture of Emca8.2 will be presented and discussed. Citation Format: John A. Colletti, Nicole L. Seiler, Maureen P. Hickman, Nyssa B. Samanas, Chrsitopher L. Warren, James D. Shull. Fine mapping and characterization of Emca8.2, a genetic determinant of susceptibility to estrogen-induced mammary cancer on chromosome 5 in the rat. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1393. doi:10.1158/1538-7445.AM2013-1393