Epigenetics of BRCA1 and Xenobiotic Sensory in Breast Cancer

Abstract

Breast cancers are the most common malignancies and leading causes of cancer mortality among women worldwide. Global breast cancer statistics reveal vast international and interethnic differences, which are attributed to non-genetic risk factors such as dietary pattern. Several lines of evidence indicate a role of the aryl hydrocarbon receptor (AhR) in breast cancer initiation and promotion of aggressive tumor phenotypes. The studies documented in this dissertation investigate the effects of the soy isoflavone genistein on oncogenic activity of the AhR in multiple in vitro and in vivo model systems. Cell culture studies investigating the effect of genistein on AhR-dependent epigenetic regulation of BRCA1 were performed in HCC38 triple negative breast cancer (TNBC) and MCF7 luminal A breast cancer cells. The effects of lifetime exposure to dietary genistein on carcinogen induced mammary tumors were investigated in a mouse model of BRCA1 mutation carriers (Brca1+/-) and wildtype littermates. The Brca1+/- model was derived using Brca1+/F22-24 mice and CRE-LOX recombination driven by transgenic expression of Cre under control of a mouse mammary tumor virus (MMTV) promoter construct. Cell culture studies demonstrated genistein reversed BRCA1 epigenetic silencing in HCC38 cells, which was attributed to antagonism toward overexpressed and hyperactive AhR. Mouse studies suggested the effect of lifetime exposure to dietary genistein on carcinogen-induced mammary tumorigenesis is dependent on genotype (Brca1+/+ vs. Brca1+/-). In Brca1+/+ mice, the genistein diet suppressed tumor growth, whereas tumor growth was enhanced in Brca1+/- mice administered genistein. These collective studies indicate the potential utility for genistein to influence epigenetic regulation of BRCA1 and antagonize AhR in mammary tumorigenesis.