Androgen receptor interacting proteins in prostate cancer development and therapy resistance

Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by the functional consequences of AR point mutations and increased expression of constitutively active receptors. Many coactivators (> 280) interact with different AR regions. Most studies have determined the expression of coactivators and their effects in the presence of increasing concentrations of androgen or the anti-androgen enzalutamide. The p160 group of coactivators (SRC-1, SRC-2, and SRC-3) is highly expressed in prostate cancer and contributes to ligand-dependent activation of the receptor in models that represent therapy-sensitive and therapy-resistant cell lines. The transcriptional coactivators p300 and CBP are implicated in the regulation of a large number of cellular events, such as proliferation, apoptosis, migration, and invasion. AR coactivators may also predict biochemical and clinical recurrence. The AR coactivator expression, which is enhanced in enzalutamide resistance, includes GREB1 and GATA2. Several coactivators also activate AR-unrelated signaling pathways, such as those of insulin-like growth factors that inhibit apoptosis in cancer cells. They are expressed in multiple models of resistance to therapy and can be targeted by various inhibitors in vitro and in vivo. The role of glucocorticoid receptor in endocrine therapy-resistant prostate cancer has been previously documented. Specific coactivators may interact with glucocorticoid receptor, thus contributing to therapy failure.