Androgen Receptor in Hormone Receptor-Positive Breast Cancer

Abstract

Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy.

Keywords: AR-targeting drugs 5; SUMOylation 4; androgen receptor 1; clinical trials 6; hormone-positive breast cancer 2; post-translational modification 3.

Figure 1

AR structure map. (A) AR linear map highlighting amino acid residues that are subject to post-translational modifications (phosphorylation, ubiquitination, and SUMOylation). Structural domains NTD, DBD, and LBD are shown here with their respective internal functional domains. (B) Crystal structure of the dimerized DBD bound to section of DNA (PDB ID: 1R4I). (C) Crystal structure of the LBD (PDB ID: 2PIW). (D) Surface representation of the LBD with AF2 domain represented in blue (PDB ID: 2PIW). (E) Ribbon representation of the LBD with helices 1, 3, 5, 11, and 12 emphasized. These helices are responsible for forming the hydrophobic pocket for the AF2 domain (PDB ID: 2PIW). (F) Structural overlay of AR LBD with different drugs/ligands bound in the ligand binding pocket.