Dataset Information

Androgen Receptor Dependence.

ABSTRACT: Androgens and the androgen receptor (AR) play crucial roles in the biology of normal and diseased prostate tissue, including prostate cancer (PCa). This dependence is evidenced by the use of androgen depletion therapy (ADT) as the primary treatment for locally advanced, metastatic, or relapsed PCa. This dependence is further evidenced by the various mechanisms employed by PCa cells to re-activate the AR to circumvent the growth-inhibitory effects of ADT. Re-activation of the AR during ADT is central to the disease evolving into the lethal castration resistant PCa (CRPC) phenotype, which is responsible for nearly all PCa mortality. Thus, understanding the regulation of AR and AR signaling is important for understanding the development and progression of PCa. This understanding provides the foundation for development of newer approaches for targeting CRPC therapeutically.

SUBMITTER: Chaturvedi AP

PROVIDER: S-EPMC8990348 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Androgen Receptor Dependence.

Chaturvedi Aashi P AP Dehm Scott M SM

Advances in experimental medicine and biology 20190101

Androgens and the androgen receptor (AR) play crucial roles in the biology of normal and diseased prostate tissue, including prostate cancer (PCa). This dependence is evidenced by the use of androgen depletion therapy (ADT) as the primary treatment for locally advanced, metastatic, or relapsed PCa. This dependence is further evidenced by the various mechanisms employed by PCa cells to re-activate the AR to circumvent the growth-inhibitory effects of ADT. Re-activation of the AR during ADT is cen ...[more]

PMID: 31900916

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Project description:BackgroundExpression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable.MethodsImmortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts.ResultsA variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s).ConclusionsRegulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome.

Project description:BackgroundProstate cancer (PRCA) is an androgen-driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR-targeted therapies, there has been a rising interest in the expression of full-length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes.MethodsDespite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full-length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning-based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments.ResultsFull-length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double-positive (AR+ /ARv7+ ) population in metastases compared to benign, and an increase of the double-negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double-positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double-negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years.ConclusionsChanges in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.

Dataset Information

Androgen Receptor Dependence.

Publications

Androgen Receptor Dependence.

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