Breast Cancer Epigenetics: Modification by Genistein

Abstract

Breast cancer it is the most common type of cancer and leading cause of cancer mortality among women worldwide. Women who inherit mutations in the breast cancer 1 susceptibility gene (BRCA1) are five times more likely to develop breast cancer than women who do not. However, only ~5-10% of breast cancer cases are due to germline mutations in tumor suppressor genes. There are currently no targeted therapies available triple negative breast cancers (TNBC), which often lack BRCA1 expression. BRCA1 is epigenetically silenced by the activated aryl-hydrocarbon receptor (AhR), suggesting that dietary antagonists of the AhR may inhibit BRCA1 silencing. Genistein is an isoflavone abundant in soy foods and its high consumption levels is thought to underlie the lower prevalence of breast cancer in Asian countries compared to Western countries. The hypothesis of this work is that genistein antagonizes AhR-dependent epigenetic silencing of BRCA1. To test this hypothesis we first determined the capacity of genistein to prevent AhR-dependent silencing of BRCA1 in estrogen receptor-alpha (ERα) expressing cells, with wild-type BRCA1 and inducible AhR (MCF-7). We also determined the effectiveness of genistein in reversing silencing of BRCA1 in ERα-negative cells with hypermethylated BRCA1 and constitutively active AhR (UACC-3199). The effect of genistein on BRCA1 promoter methylation and markers of cell proliferation was also determined in both cell lines.