Abstract 1391: Cellular and molecular bases of susceptibility to estrogen-induced mammary cancer in the rat.

Abstract

Abstract Known breast cancer risk factors include a family history of breast cancer, cumulative exposure to endogenous and exogenous estrogens and breast mammographic density. Although several genes have been identified that significantly impact risk when mutated or aberrantly expressed, the genetic determinants of responsiveness to estrogens and mammographic density remain poorly defined. We are using the ACI rat model of 17β-estradiol (E2)-induced mammary cancer to identify genetic and environmental determinants of susceptibility to mammary cancer. When treated continuously with physiologic levels of E2, female ACI rats develop mammary carcinoma at an incidence approaching 100%. The mammary cancers that develop in E2 treated ACI rats express estrogen receptor-α (ERα) and progesterone receptor (PgR) and are dependent upon E2 for continued growth. By contrast, Brown Norway (BN) rats are highly resistant to E2-induced mammary cancer. The purpose of this study was to compare the impact of E2 treatment on mammary gland biology in susceptible ACI and resistant BN rats. Dramatic differences in numerous cellular and molecular responses to E2 were observed when these two inbred rat strains were compared. Whereas the mammary epithelium of susceptible ACI rats exhibited a marked proliferative response to E2, the epithelium of resistant BN rats exhibited responses associated with differentiation to secretory epithelium. Strain differences in expression of multiple genes associated with mammary epithelial cell proliferation and differentiation were observed. Specifically, Areg, Pgr, Wnt4 and Tnfsf11 were highly expressed in mammary glands of E2 treated ACI rats, relative to treated BN rats, whereas Lcn2, Spp1, Cd44, Mmp7 and Mmp9 were highly expressed in mammary glands of BN rats, relative to ACI rats. This study provides novel insight into the molecular bases of inherited susceptibility to E2-induced mammary cancer. We further propose that the observed strain differences in mammary gland responsiveness to E2 represent phenotypes that underlie variation in mammographic density in humans and may have the potential to serve as biomarkers that predict breast cancer risk. Citation Format: Lina Ding, Yang Zhao, Christopher Warren, James Shull. Cellular and molecular bases of susceptibility to estrogen-induced mammary cancer 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 1391. doi:10.1158/1538-7445.AM2013-1391