Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Jun 21:17:211-223.
doi: 10.2147/RRU.S388265. eCollection 2025.

Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies

Alberto Quistini #  1 , Francesco Chierigo #  2 , Giuseppe Fallara  2 , Massimiliano Depalma  2 , Marco Tozzi  2 , Martina Maggi  2 , Letizia Maria Ippolita Jannello  2 , Francesco Pellegrino  2 , Guglielmo Mantica  3 , Daniela Terracciano  4 , Rocco Papalia  5 , Felice Crocetto  6 , Rocco Damiano  7 , Roberto Bianchi  2 , Bernardo Maria Rocco  8 , Matteo Ferro  2
Affiliations
Review

Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies

Alberto Quistini et al. Res Rep Urol. .

Abstract

Prostate cancer (PCa) is a major global health concern. It ranks as the fifth leading cause of cancer-related mortality worldwide. While localized PCa is often indolent, with a nearly 100% five-year survival rate, prognosis worsens significantly in metastatic disease, where survival drops to approximately 30%. Androgen deprivation therapy (ADT) is initially effective in suppressing tumor growth. However, resistance eventually develops, resulting in castration-resistant prostate cancer (CRPC). The androgen receptor (AR) plays a central role in both PCa progression and treatment resistance. It promotes tumor growth by mediating the effects of testosterone and 5α-dihydrotestosterone (DHT). Several mechanisms contribute to resistance. These include AR gene mutations that reduce ligand specificity or convert antagonists into agonists. AR overexpression can maintain activity even at low androgen levels. Splice variants such as AR-V7 can activate AR signaling despite androgen depletion. AR transcriptional activity is also modulated by coregulators. Coactivators (such as the SRC family) and corepressors (such as NCOR1/2) contribute to the persistence of AR signaling. Beyond AR-dependent mechanisms, CRPC may develop through AR-independent pathways. These include glucocorticoid receptor (GR) bypass signaling and lineage plasticity leading to neuroendocrine prostate cancer (NEPC). In addition, intratumoral steroidogenesis sustains AR activation despite systemic suppression of androgens. Together, these resistance mechanisms underscore the biological complexity of CRPC. They also highlight the urgent need for innovative therapeutic approaches. This manuscript reviews emerging molecular targets and resistance pathways to inform the development of next-generation treatments.

Keywords: ADT; AR; CRPC; androgen deprivation therapy; androgen receptor; castration-resistant prostate cancer; prostate cancer; therapeutic resistance.

PubMed Disclaimer

Conflict of interest statement

Alberto Quistini and Francesco Chierigo are co-first authors for this study. The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Timeline of key translational discoveries and therapeutic innovations in the treatment of PCa.
Figure 2
Figure 2
AR Gene and Protein structure.
See this image and copyright information in PMC

References

    1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12–49. doi: 10.3322/caac.21820 - DOI - PubMed
    1. Aurilio G, Cimadamore A, Mazzucchelli R, et al. Androgen receptor signaling pathway in prostate cancer: from genetics to clinical applications. Cells. 2020;9(12):1–14. doi: 10.3390/cells9122653 - DOI - PMC - PubMed
    1. Huggins C, Hodges CV. Studies on prostatic cancer: i. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168(1):9–12. doi: 10.1016/s0022-5347(05)64820-3 - DOI - PubMed
    1. Scher HI, Buchanan G, Gerald W, Butler LM, Tilley WD. Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer. Endocr Relat Cancer. 2004;11(3):459–476. doi: 10.1677/erc.1.00525 - DOI - PubMed
    1. Thoreson GR, Gayed BA, Chung PH, Raj GV.Emerging therapies in castration resistant prostate cancer. Can J Urol. 2014;21(2):98–105. - PubMed

LinkOut - more resources