Endocrine Abstracts

Estrogen receptors (ER) are expressed in the majority of breast cancers, are key drivers of breast cancer development and progression and hence therapies to inhibit their activities are a mainstay of treatment for breast cancer. A large proportion of patients develop resistance to these therapies, so determining the mechanisms of ER action is important for improving patient management and for identifying new therapies. In defining the mechanisms by which ER regulates gene expression, we and others find that proteins involved in DNA damage recognition and repair (DDR), including components of base excision repair (BER) and non-homologous end-joining (NHEJ) are central to the promotion of gene expression by ER. Most recently, we have demonstrated that the cytosine deaminase APOBEC3B (A3B) is recruited to the regulatory regions of estrogen-responsive genes in an ER-dependent manner. We have shown that A3B recruitment promotes transient C-to-U changes at ER/A3B binding regions, repaired by BER/NHEJ pathways, with the cytosine deamination and its repair facilitating chromatin remodeling that aids expression of ER target genes. Importantly, we have now extended these studies to demonstrate an important role for A3B in transcription regulation in ER-negative, as well as ER-positive breast cancer cell lines, indicating that A3B has a general role in regulating gene expression in human cells. These findings highlight the therapeutic potential of A3B inhibitors for the treatment of ER+ and ER-negative breast cancer. Recent reports have implicated A3B as the enzyme responsible for acquisition of mutations and tumour evolution in diverse cancer types, highlighting the inherent dangers associated with the cellular role of DNA damage and repair in the regulation of gene expression. These findings also raise the question of whether targeting of A3B to gene regulatory regions might promote non-coding mutations that modify gene enhancer function and provide further impetus for the development of A3B inhibitors for cancer.