Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy

► SRCs interact with and promote NR-mediated transcriptional activation by recruiting co-coactivators to their activation domains. ► SRC-1 and SRC-3 drive tumorigenesis and are particularly overexpressed in breast cancer. ► SRC-1 and SRC-3 negatively correlate with overall and disease-free survival and positively with tamoxifen resistance. ► Tumors may develop resistance to SRMs through overexpression or cell signaling-mediated activation of coactivators, like SRCs. ► Coactivators may promote resistance in NR-dependent and independent cancers making coactivator-specific inhibitors promising candidates.