Cytidine Deaminases are Regulators of Estrogen Receptor Activity in Breast Cancer Cells

Abstract

Breast cancer is the most common cancer worldwide, with 1.38 million women diagnosed with the disease each year. Estrogens play a critical role in the development and progression of breast cancer, their action being mediated by the estrogen receptors (ER), ERα and ERß, which are the members of the nuclear receptor superfamily of transcription factors. This understanding has led to the development of endocrine therapies aimed at inhibiting ER action by competitive binding to the ER (anti-estrogens), or using inhibitors of estrogen biosynthesis (aromatase inhibitors). Determining the mechanisms by which ER regulate gene expression will aid our understanding of the role of ER in breast cancer progression, response and resistance to endocrine therapies. Upon binding estrogen, ER drives the expression of estrogen responsive genes through the orderly recruitment of co-regulators that act by remodelling and modifying chromatin, ultimately promoting RNA polymerase II recruitment and transcription initiation. Previous work from our laboratory has shown that the APOBEC3B cytosine deaminase acts as an ERα transcriptional coactivator in reporter gene assays. Here, I have developed these initial observations and demonstrate that APOBEC3B is important for the regulation of estrogen responsive genes and breast cancer cell growth. I show that APOBEC3B is recruited to the promoters of estrogen-responsive genes and interacts with ERα. Studies carried out to identify the molecular mechanisms by which APOBEC3B regulates the expression of estrogen-responsive genes included its potential role in DNA demethylation and identified a role for APOBEC3B in DNA strand break formation at the promoter of the estrogen regulated pS2 gene. Together, these studies identify APOBEC3B as an important new coregulator of ERα that is required for the regulation of gene expression by estrogen in breast cancer cells.