Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

Exploring epigenetic gene essentiality identifying key regulators of cell survival represents a promising way to exploit new targets to overcome resistance to current pharmacological regimens. In breast cancer (BC), endocrine therapy (ET) resistance arises from aberrant Estrogen Receptor alpha (ERa) signaling and targeting cancer cell vulnerability within the ERa pathway represents a rationale for development of effective new drugs against this disease. By combining bioinformatics analysis of genome-wide 'drop-out' screenings and siRNA-mediated gene knock-down (kd) we identified a set of essential genes that includes, as the most effective, the bromodomain containing protein BRPF1. BRPF1 belongs to a family of epigenetic readers acting as chromatin remodelers to control gene transcription. To gather mechanistic insight into the role of this epienzyme in BC, we applied chromatin and transcriptome profiling, gene ablation and specific pharmacological inhibition followed by cellular and functional assays. Experimental evidences indicate that BRPF1 associates with ERa in MCF-7 cells chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through modulation of chromatin accessibility. This results in a widespread inhibition of ER-dependent hormonal signaling obtained by ERa gene silencing in AE-sensitive and -resistant BC cells and pre-clinical patient-derived models (PDO). The characterization of functional interplays between ERa and BRPF1 revealed a new master regulator of BC survival, providing a rationale for a BRPF1 targeted cancer diagnosis and highlighting a new therapeutic vulnerability for the treatment of these aggressive tumors.