Endocrine resistance and breast cancer plasticity are controlled by CoREST

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant for endocrine resistance and ER+ breast cancer plasticity. In endocrine sensitive cells, CoREST is recruited to ERα/FOXA1 co-bound regulatory regions to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit, LSD1. Genetic and pharmacological CoREST inhibition reduce tumorigenesis and metastasis of endocrine sensitive and resistant xenografts models. Consistently, CoREST controls a gene signature in clinical breast tumors resistant to endocrine therapies involved in invasiveness. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.