Oestrogens promote breast cancer development and progression by binding to the oestrogen receptors. Oestrogen receptor-alpha (ER) is a transcription regulatory protein that is activated upon binding oestrogen and acts by controlling gene expression in breast cancer cells and is the target for endocrine therapies that inhibit its activity by competing with oestrogen for binding to ER (anti-oestrogens) or by inhibiting oestrogen biosynthesis (aromatase inhibitors). These therapies have contributed to the decline in breast cancer mortality in recent years. However, many patients either do not respond, or eventually relapse, necessitating a better understanding of the mechanisms of gene regulation by ER, towards improved patient stratification and the development of drugs for the treatment of advanced breast cancer.
Gene regulation by ER requires the concerted action of diverse chromatin remodelling and histone modification enzymes, acting at the regulatory regions of ER target genes. Thus epigenetic drivers play essential roles in oestrogen action in breast cancer. Interestingly, we have also demonstrated the importance of DNA repair enzymes in the regulation of ER target gene expression. In particular, we have shown that DNA strand break generation is integral to chromatin remodelling/modification in gene regulation by ER. These findings and their implications for the treatment of ER-positive breast cancer will be presented.