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Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities

Nature Reviews Cancer volume 25, pages 93–108 (2025)Cite this article

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Abstract

The androgen receptor (AR) signalling pathway has been intensively studied in the context of prostate cancer, where androgen deprivation therapy is part of the standard of care for metastatic disease. By contrast, fewer studies have investigated the impact and translational potential of targeting AR in other cancer types where it is also expressed and functional. In this Review, we discuss the current understanding of AR in non-prostatic cancer types and summarize ongoing AR-directed clinical trials. While different androgen levels contribute to sexual dimorphism in cancer, targeting the AR system could benefit both sexes and help overcome resistance to targeted therapies. However, a bimodal function of AR signalling, which suppresses stromal changes associated with the early stages of cancer development, also needs to be considered. Future research is necessary to scrutinize cellular and molecular mechanisms of action of AR in cancer cells and the tumour microenvironment, to develop selective modulators of AR activity, and to identify patients with non-prostatic cancer who might benefit from targeting this pathway. AR-directed manipulation of host immune cells may offer a promising therapeutic approach for many types of cancers.

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Fig. 1: Androgens and AR signalling, production and major functions.
Fig. 2: Cell-intrinsic actions of AR.
Fig. 3: Role of AR in the TME.

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Acknowledgements

We express our gratitude to Z. Li, C. Brisken, W. Zwart and G. Tolstonog for critical reading of the manuscript and insightful suggestions. Research in the laboratory of G.B.D. is supported by NIH grants R01AR078374 and R01CA269356 (the contents do not necessarily represent the official views of the NIH).

Author information

Authors and Affiliations

  1. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    G. Paolo Dotto

  2. Service d’Oto-rhino-laryngologie et chirurgie cervical faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne (UNIL), Lausanne, Switzerland

    G. Paolo Dotto & Christian Simon

  3. International Cancer Prevention Institute, Epalinges, Switzerland

    G. Paolo Dotto & An Buckinx

  4. Department of Medical Oncology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland

    Berna C. Özdemir

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  1. G. Paolo Dotto
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  2. An Buckinx
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  3. Berna C. Özdemir
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  4. Christian Simon
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All authors researched data, contributed substantially to discussion of the content, and participated in the writing of the article and reviewing it before submission.

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Correspondence to G. Paolo Dotto.

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Nature Reviews Cancer thanks Dong Gao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Androgen deprivation therapy

(ADT). A treatment that reduces androgen levels to slow the growth of androgen-dependent cancers such as prostate cancer.

Anitens

A class of small-molecule inhibitors that target the N-terminal domain of the androgen receptor (AR), currently being tested in the treatment for prostate cancer.

Bacillus Calmette–Guérin

A live-attenuated strain of Mycobacterium bovis used as a vaccine against tuberculosis and in the treatment of non-muscle-invasive bladder cancer.

Dimensionality reduction

Techniques that reduce the number of input variables in a data set while retaining essential information, often to simplify models or improve visualization.

Endocrine therapy

Treatment that targets hormone pathways to inhibit the growth of hormone-sensitive cancers such as breast or prostate cancer.

Four core genotypes model

A mouse model used to study the effects of sex chromosomes and gonadal hormones independently of one another.

Glial cells

Supportive cells in the nervous system that maintain homeostasis, form myelin, and provide protection and support to neurons.

Group 2 innate lymphoid cells

Immune cells that lack antigen-specific receptors and play a role in innate immunity, including in allergic responses and cancer.

Immediate-early effects

Rapid cellular responses to stimuli that do not require new protein synthesis, often occurring within minutes of activation.

Leydig cells

Cells in the testes that produce testosterone in response to luteinizing hormone.

Linear support vector classifiers

A classification algorithm that finds the optimal hyperplane separating data into different classes in a high-dimensional space.

Pioneer factors

Transcription factors that access condensed chromatin to enable gene expression during cell differentiation or reprogramming.

Primary sex characteristics

Biological traits directly involved in reproduction such as the testes and ovaries.

Proteolysis-targeting chimaeras

Bifunctional molecules designed to target specific proteins for degradation via the ubiquitin–proteasome system.

Recurrent neural networks

A type of neural network designed to recognize patterns in sequences of data by using internal memory and feedback loops to process inputs over time.

Secondary sex characteristics

Physical traits that develop during puberty but are not directly involved in reproduction (such as facial hair and breast development).

Selective AR modulators

Compounds that selectively stimulate or inhibit ARs in different tissues to provide anabolic effects with reduced side effects.

Senescence

A state of irreversible cell cycle arrest that acts as a cancer-protective mechanism but can also promote tumorigenesis through pro-inflammatory secretions.

Senescence-associated secretory phenotype

(SASP). A pro-inflammatory and tissue-remodelling secretion profile produced by senescent cells that can influence cancer progression.

Supervised learning

A machine learning approach where a model is trained on labelled data to learn a mapping from inputs to outputs.

Theca cells

Ovarian cells that produce androgens, which are converted to oestrogens by granulosa cells during follicle development.

Tumour-associated macrophages

(TAMs). Macrophages present in the tumour microenvironment that can promote tumour growth, immune evasion and metastasis.

Zona reticularis cells

Cells in the adrenal cortex that primarily secrete androgens like dehydroepiandrosterone.

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Dotto, G.P., Buckinx, A., Özdemir, B.C. et al. Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities. Nat Rev Cancer 25, 93–108 (2025). https://doi.org/10.1038/s41568-024-00772-w

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