title: 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.
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Hoang
authors.affiliation: Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Iczkowski
authors.affiliation: Department of Medicine, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kilari
authors.affiliation: Department of Urology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: William
authors.initials: W
authors.lastname: See
authors.affiliation: Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.|Department of Pharmacology/Toxicology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008024:Ligands; D008297:Male; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D059002:Androgen Receptor Antagonists; D008024:Ligands; D011944:Receptors, Androgen; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2
keywords: Jak2; Stat5a/b; androgen receptor; antiandrogen; castrate-resistant; metastasis; prostate cancer