Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

Abstract

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.

IL‐1 induces p62/SQSTM1 and autophagy in ERα+/PR+ BCa cell lines concomitant with ERα and PR repression, conferring an ERα−/PR− BCa‐like phenotype

“…AR is a nuclear hormone receptor that promotes PCa growth and proliferation and, thus, is a PCa therapeutic target . However, as with ERα low/− BCa tumors, PCa tumors enriched in AR low/− cells are associated with hormone therapy resistance . Furthermore, as with BCa, IL‐1 also promotes PCa metastasis to bone and IL‐1 is implicated in PCa hormone therapy resistance .…”

“…24 However, as with ERα low/− BCa tumors, PCa tumors enriched in AR low/− cells are associated with hormone therapy resistance. 24,25 Furthermore, as with BCa, IL-1 also promotes PCa metastasis to bone 26 and IL-1 is implicated in PCa hormone therapy resistance. 27 Therefore, given the etiological similarities between BCa and PCa, we hypothesize that the IL-1 mechanisms that promote resistance to hormone receptor-targeting therapies are similar in BCa and PCa.…”

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…The androgen-independent pathway includes: (1) AR gain-function mutations; (2) activation by nonandrogen steroids or androgen antagonists; (3) activation by non-steroid growth factors (receptor tyrosine kinases are activated and both AKT and MAPK pathways, producing a ligand-independent AR); and (4) increase of AR co-regulators. A parallel survival pathway, involving the anti-apoptotic protein BCL-2, also induces the cancer cell proliferation via bypassing the AR [183,184] . AR: androgen receptor; GnRH: gonadotropin-releasing hormone analogues; T: testosterone; DHT: dihydrotestosterone; ARE: androgen response element; DHEA: dehydroepiandrosterone; LH: luteinizing hormone; ACTH: adreno-cortico-tropic-hormone…”

Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer

“…Androgen‐dependent processes contributing to recurrence include AR amplification, intratumoral androgen synthesis, altered AR cofactor expression, or AR mutation leading to ligand promiscuity . Alternatively, recurrence can occur through androgen‐independent mechanisms including growth factor‐mediated AR signaling and the expansion of AR‐negative cell types (ie, PRCA stem‐like cells, neuroendocrine PRCA cells, double‐negative PRCA) . Recent evidence has supported the emergence of AR splice variant 7 (ARv7) expression in advanced disease and recurrence .…”

“…[6][7][8][9] Alternatively, recurrence can occur through androgen-independent mechanisms including growth factor-mediated AR signaling and the expansion of AR-negative cell types (ie, PRCA stemlike cells, neuroendocrine PRCA cells, double-negative PRCA). [10][11][12][13][14] Recent evidence has supported the emergence of AR splice variant 7 (ARv7) expression in advanced disease and recurrence. [15][16][17] ARv7 lacks the ligand-binding domain of full-length AR and thus does not require ligand to translocate to the nucleus.…”