Pharmacological chromatin remodeling enhances response to estrogen therapy in ER+ breast cancer.

Estrogen therapy elicits clinical benefit in ~ 30% of patients with endocrine-resistant estrogen receptor (ER)-positive breast cancer, but its mechanism of action and strategies to increase efficacy remain unclear. Estrogen therapy can induce ER transcriptional hyperactivation and DNA damage; we postulated that such damage could be exacerbated by epigenetic dysregulation via inhibition of histone deacetylases (HDACi). We evaluated the effects of 17b-estradiol and HDACi in three types of ER+ breast cancer models: Cells adapted to growth following long-term estrogen deprivation; cells engineered to overexpress exogenous ER that confers endocrine resistance; mice bearing endocrine-resistant patient-derived xenografts. Assay endpoints included apoptosis, growth, DNA damage, histone post-translational modification, levels of ER-regulated transcripts and encoded proteins, cell cycle and replication status, and genome-wide chromatin accessibility, ER binding, and transcriptional profiles. Entinostat treatment increased histone acetylation and chromatin accessibility. Combination treatment with E2 and entinostat inhibited cell growth and induced apoptosis in ER-overexpressing models. E2 and entinostat induced DNA damage as single agents and in combination. These agents synergized against tumor models, offering HDACi as a strategy to enhance efficacy of estrogen therapy.