Role of the androgen receptor in urothelial cancer

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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Role of pomegranate extract in restoring endometrial androgen receptor expression, proliferation, and pinopodes in a rat model of polycystic ovary syndrome

Morphologie ◽

10.1016/j.morpho.2021.04.004 ◽

2021 ◽

Author(s):

M.A.A. Ibrahim ◽

M.T. Sadek ◽

H.E.M. Sharaf Eldin

Keyword(s):

Androgen Receptor ◽

Polycystic Ovary Syndrome ◽

Rat Model ◽

Polycystic Ovary ◽

Receptor Expression ◽

Androgen Receptor Expression ◽

Ovary Syndrome

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Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-020-00309-w ◽

2021 ◽

Author(s):

M. Del Re ◽

V. Conteduca ◽

S. Crucitta ◽

G. Gurioli ◽

C. Casadei ◽

...

Keyword(s):

Androgen Receptor ◽

Clinical Outcome ◽

Liquid Biopsy ◽

Response To Treatment ◽

First Line ◽

Primary Resistance ◽

Circulating Free Dna ◽

Free Dna ◽

Signaling Inhibitors

Abstract Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

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Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Cells ◽

10.3390/cells10051169 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1169

Author(s):

Hiroki Ide ◽

Hiroshi Miyamoto

Keyword(s):

Bladder Cancer ◽

Estrogen Receptor ◽

Androgen Receptor ◽

Surgical Therapy ◽

Urothelial Cancer ◽

Hormone Receptors ◽

Estrogen Receptor Α ◽

Vital Role ◽

Sex Hormone ◽

Sex Steroid Hormone

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

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