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

Santrauka

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.