Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

Abstract

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.

Prostate Cancer—Focus on Cholesterol

“…PI3K/Akt/mTOR signaling is antagonized by the tumor suppressor phosphatases and tensin homolog (PTEN) [ 118 ]. PTEN deletions and/or mutations are present in up to 30% of primary and 63% of metastatic PC [ 119 , 120 ]. PTEN loss upregulates PI3K/AKT/mTOR pathway which in turn upregulates SREBP and LDLR in PC cells, which leads to androgen independent accumulation of cholesteryl ester in high-grade and metastatic human PC [ 87 ].…”

The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells

“…Although androgen deprivation therapies (ADT) are effective and remain a common treatment for patients, castration resistant PCa (CRPC) inevitably develops as both epigenetic and genetic alterations allow the PCa to bypass therapeutic interventions. Therefore, many studies have focused on how AR is overexpressed, modified by mutation, or differentially spliced to drive the AR signaling axis under ADT and promote cancer growth [ 2 , 3 ]. While the clinical significance of AR mediated gene activation in PCa has been widely reported, for example overexpression of the TMPRSS2-ERG fusion gene, there is considerably less attention paid to the AR as a direct transcriptional repressor and how this role is implicated in PCa progression.…”

“…The tumor suppressive effects of estrogens were originally thought to be facilitated by estrogen receptors ERα and ERβ, but recent research from our lab has identified a third ER, G-protein Estrogen Receptor 1 (GPER1), that plays a critical role in suppressing PCa growth [17]. Specific activation GPER1 by the drug G-1 (1(1-[4-(6-bromobenzo [1,3]dioxol-5-yl)-3a,4,5,9btetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) inhibited tumor growth and led to 60% necrosis of CRPC LNCaP-derived xenografts in castrated mice [17]. Interestingly, G-1, a GPER1 agonist, showed no effect in the parental androgen-dependent PCa of non-castrated mice [17].…”

Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

“…This includes activation of PI3K-AKT-mTOR signaling, which is a well-known pathway that regulates multiple signal transductions and biological processes such as transcription, protein synthesis, metabolism, autophagy, cell proliferation, apoptosis, angiogenesis, migration, etc. [11][12][13][14][15][16]. In this review, we highlight the role of PI3K-AKT-mTOR signaling as a resistance mechanism for PCa therapy in both AR dependent and independent manners.…”