Stranger Things: New Roles and Opportunities for Androgen Receptor in Oncology Beyond Prostate Cancer

Abstract

The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor's potential as a therapeutic target and will help guide the development of new treatment approaches.

Keywords: adrenal cancer; androgen receptor; bladder cancer; breast cancer; endometrial cancer; liver cancer; melanoma; prostate cancer.

Figure 1.

AR promotes resistance to BRAF and MEK inhibitors in BRAF-mutant melanomas. Patients harboring BRAF-mutant melanoma are treated with BRAF and MEK inhibitors (BRAF/MEKi). Treatment-resistant BRAF-mutant melanomas exhibit increased expression and activity of the androgen receptor (AR).

Figure 2.

Procancer and anticancer roles for AR in HCC. Schematic of reported contrasting roles for AR in HCC. ACP5, tartrate-resistant acid phosphatase type 5; AR, androgen receptor; ERα, estrogen receptor α; FOXA1, forkhead box protein A1; HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; RABL6, Rab-like protein 6.

Figure 3.

Subtype-specific roles for AR in breast cancer. Schematic of reported roles for AR in ERα+, HER2+ and triple-negative breast cancer. AR, androgen receptor; BrCa, breast cancer; ERα, estrogen receptor α; TNBC. Triple-negative breast cancer. Figure created with BioRender.com.

Figure 4.

Effects of obesity of steroidogenesis. Indicated in blue on the right are the steroid metabolites that have been reported to be increased in obese individuals. Shown in italics are steroidogenic enzymes. AR, androgen receptor; ER, estrogen receptor; SARM, selective androgen receptor modulator; SERD, selective estrogen receptor degrader; SERMs, selective estrogen receptor modulator.