Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The androgen receptor in bladder cancer

Nature Reviews Urology volume 20, pages 560–574 (2023)Cite this article

Subjects

Abstract

Bladder cancer is the ninth most common cancer worldwide with a striking sex-based difference in incidence. Emerging evidence indicates that the androgen receptor (AR) might promote the development, progression and recurrence of bladder cancer, contributing to the observed sex differences. Targeting androgen–AR signalling has promise as potential therapy for bladder cancer and helps to suppress progression of this disease. In addition, the identification of a new membrane AR and AR-regulated non-coding RNAs has important implications for bladder cancer treatment. The success of human clinical trials of targeted-AR therapies will help in the development of improved treatments for patients with bladder cancer.

Key points

  • The androgen receptor (AR) promotes bladder cancer development and progression through various molecular mechanisms, contributing to the observed sex difference in bladder cancer incidence.

  • The identification of the second membrane AR and AR-related non-coding RNAs provides novel therapeutic targets for bladder cancer treatment.

  • AR signalling can mediate resistance to cisplatin-based chemotherapy and BCG immunotherapy, providing a rationale to combine AR-targeted therapy with chemotherapy or BCG in bladder cancer.

  • Results of investigation into CD8+ T cell-intrinsic AR activity suggest that the roles of AR in other immune cells are worthy of investigation.

  • Future work addressing the interaction between anti-PD1 and anti-PDL1 immunotherapy and AR signalling in bladder cancer is needed to guide clinical therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Androgen-dependent and androgen-independent activation of AR.
Fig. 2: AR promotes bladder cancer cell proliferation.
Fig. 3: AR promotes bladder cancer cell invasion and metastasis.
Fig. 4: AR affects bladder progression via interacting with or regulating non-coding RNAs.

Similar content being viewed by others

References

  1. Richters, A., Aben, K. K. H. & Kiemeney, L. The global burden of urinary bladder cancer: an update. World J. Urol. 38, 1895–1904 (2020).

    Article  PubMed  Google Scholar 

  2. Lobo, N. et al. What is the significance of variant histology in urothelial carcinoma? Eur. Urol. Focus. 6, 653–663 (2020).

    Article  PubMed  Google Scholar 

  3. Lenis, A. T., Lec, P. M., Chamie, K. & Mshs, M. D. Bladder cancer: a review. JAMA 324, 1980–1991 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Cumberbatch, M. G., Cox, A., Teare, D. & Catto, J. W. Contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis. JAMA Oncol. 1, 1282–1290 (2015).

    Article  PubMed  Google Scholar 

  5. Cumberbatch, M. G. K. et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. Eur. Urol. 74, 784–795 (2018).

    Article  PubMed  Google Scholar 

  6. Babjuk, M. et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur. Urol. 81, 75–94 (2022).

    Article  PubMed  Google Scholar 

  7. Witjes, J. A. et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur. Urol. 79, 82–104 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Tran, L., Xiao, J. F., Agarwal, N., Duex, J. E. & Theodorescu, D. Advances in bladder cancer biology and therapy. Nat. Rev. Cancer 21, 104–121 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Rey-Cardenas, M. et al. Recent advances in neoadjuvant immunotherapy for urothelial bladder cancer: what to expect in the near future. Cancer Treat. Rev. 93, 102142 (2021).

    Article  CAS  PubMed  Google Scholar 

  10. Antoni, S. et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur. Urol. 71, 96–108 (2017).

    Article  PubMed  Google Scholar 

  11. Gul, Z. G., Liaw, C. W. & Mehrazin, R. Gender differences in incidence, diagnosis, treatments, and outcomes in clinically localized bladder and renal cancer. Urology 151, 176–181 (2021).

    Article  PubMed  Google Scholar 

  12. Dobruch, J. et al. Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur. Urol. 69, 300–310 (2016).

    Article  PubMed  Google Scholar 

  13. Krabbe, L. M., Svatek, R. S., Shariat, S. F., Messing, E. & Lotan, Y. Bladder cancer risk: use of the PLCO and NLST to identify a suitable screening cohort. Urol. Oncol. 33, 65.e19–25 (2015).

    Article  PubMed  Google Scholar 

  14. Zhang, Y. Understanding the gender disparity in bladder cancer risk: the impact of sex hormones and liver on bladder susceptibility to carcinogens. J. Env. Sci. Health C. Env. Carcinog. Ecotoxicol. Rev. 31, 287–304 (2013).

    Article  CAS  Google Scholar 

  15. Karagas, M. R. et al. Gender, smoking, glutathione-S-transferase variants and bladder cancer incidence: a population-based study. Cancer Lett. 219, 63–69 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Hu, D. G., Mackenzie, P. I., McKinnon, R. A. & Meech, R. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug. Metab. Rev. 48, 47–69 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Yu, C. et al. GSTM1 and GSTT1 polymorphisms are associated with increased bladder cancer risk: evidence from updated meta-analysis. Oncotarget 8, 3246–3258 (2017).

    Article  PubMed  Google Scholar 

  18. Salinas-Sánchez, A. S. et al. Polymorphic deletions of the GSTT1 and GSTM1 genes and susceptibility to bladder cancer. BJU Int. 107, 1825–1832 (2011).

    Article  PubMed  Google Scholar 

  19. Chang, C. S., Kokontis, J. & Liao, S. T. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240, 324–326 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Chang, C., Lee, S. O., Yeh, S. & Chang, T. M. Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene 33, 3225–3234 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Huang, Q. et al. Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma. Nat. Commun. 8, 918 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. You, B. et al. Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR. Oncogene 40, 1674–1689 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kono, M. et al. Androgen receptor function and androgen receptor-targeted therapies in breast cancer: a review. JAMA Oncol. 3, 1266–1273 (2017).

    Article  PubMed  Google Scholar 

  24. Ma, W. L. et al. Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology 56, 176–185 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Berardi, R. et al. Hormonal receptors in lung adenocarcinoma: expression and difference in outcome by sex. Oncotarget 7, 82648–82657 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Solomon, Z. J. et al. Selective androgen receptor modulators: current knowledge and clinical applications. Sex. Med. Rev. 7, 84–94 (2019).

    Article  PubMed  Google Scholar 

  27. Laor, E. et al. Androgen receptors in bladder tumors. Urology 25, 161–163 (1985).

    Article  CAS  PubMed  Google Scholar 

  28. Mashhadi, R. et al. Role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study. Urol. J. 11, 1968–1973 (2014).

    PubMed  Google Scholar 

  29. Tuygun, C. et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urol. Oncol. 29, 43–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Boorjian, S. et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology 64, 383–388 (2004).

    Article  PubMed  Google Scholar 

  31. Miyamoto, H. et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 109, 1716–1726 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Kauffman, E. C. et al. Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol. Carcinog. 50, 931–944 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Miyamoto, H. et al. Promotion of bladder cancer development and progression by androgen receptor signals. J. Natl Cancer Inst. 99, 558–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Hsu, J. W. et al. Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor. Am. J. Pathol. 182, 1811–1820 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnson, D. T. et al. Conditional expression of the androgen receptor increases susceptibility of bladder cancer in mice. PLoS ONE 11, e0148851 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Davey, R. A. & Grossmann, M. Androgen receptor structure, function and biology: from bench to bedside. Clin. Biochem. Rev. 37, 3–15 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Lombard, A. P. & Mudryj, M. The emerging role of the androgen receptor in bladder cancer. Endocr. Relat. Cancer 22, R265–R277 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Keast, J. R. & Saunders, R. J. Testosterone has potent, selective effects on the morphology of pelvic autonomic neurons which control the bladder, lower bowel and internal reproductive organs of the male rat. Neuroscience 85, 543–556 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Shortliffe, L. M., Ye, Y., Behr, B. & Wang, B. Testosterone changes bladder and kidney structure in juvenile male rats. J. Urol. 191, 1913–1919 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Tek, M. et al. The effect of testosterone replacement therapy on bladder functions and histology in orchiectomized mature male rats. Urology 75, 886–890 (2010).

    Article  PubMed  Google Scholar 

  41. Gelmann, E. P. Molecular biology of the androgen receptor. J. Clin. Oncol. 20, 3001–3015 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Huang, C. F. et al. Functional mapping of androgen receptor enhancer activity. Genome Biol. 22, 149 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van de Wijngaart, D. J., Dubbink, H. J., van Royen, M. E., Trapman, J. & Jenster, G. Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol. Cell Endocrinol. 352, 57–69 (2012).

    Article  PubMed  Google Scholar 

  44. Ueda, T., Bruchovsky, N. & Sadar, M. D. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J. Biol. Chem. 277, 7076–7085 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Seaton, A. et al. Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. Carcinogenesis 29, 1148–1156 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Culig, Z. et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 54, 5474–5478 (1994).

    CAS  PubMed  Google Scholar 

  47. Wu, J. D. et al. Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J. Cell Biochem. 99, 392–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Mudryj, M. & Tepper, C. G. On the origins of the androgen receptor low molecular weight species. Horm. Cancer 4, 259–269 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lamont, K. R. & Tindall, D. J. Minireview: alternative activation pathways for the androgen receptor in prostate cancer. Mol. Endocrinol. 25, 897–907 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Overdevest, J. B. et al. CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated. Proc. Natl Acad. Sci. USA 109, E3588–E3596 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ding, G., Yu, S., Cheng, S., Li, G. & Yu, Y. Androgen receptor (AR) promotes male bladder cancer cell proliferation and migration via regulating CD24 and VEGF. Am. J. Transl. Res. 8, 578–587 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Agarwal, N. et al. GON4L drives cancer growth through a YY1-androgen receptor-CD24 axis. Cancer Res. 76, 5175–5185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Izumi, K., Zheng, Y., Li, Y., Zaengle, J. & Miyamoto, H. Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. Int. J. Oncol. 41, 1587–1592 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hsieh, T. F. et al. Epidermal growth factor enhances androgen receptor-mediated bladder cancer progression and invasion via potentiation of AR transactivation. Oncol. Rep. 30, 2917–2922 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Yang, Z. et al. Androgen receptor suppresses prostate cancer metastasis but promotes bladder cancer metastasis via differentially altering miRNA525-5p/SLPI-mediated vasculogenic mimicry formation. Cancer Lett. 473, 118–129 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Xiong, Y. et al. The long non-coding RNA XIST interacted with MiR-124 to modulate bladder cancer growth, invasion and migration by targeting androgen receptor (AR). Cell Physiol. Biochem. 43, 405–418 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Chen, J. et al. Androgen receptor-regulated circFNTA activates KRAS signaling to promote bladder cancer invasion. EMBO Rep. 21, e48467 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mir, C. et al. Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study. BJU Int. 108, 24–30 (2011).

    Article  PubMed  Google Scholar 

  59. Jing, Y. et al. Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition. Cancer Lett. 348, 135–145 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Nam, J. K., Park, S. W., Lee, S. D. & Chung, M. K. Prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer. Yonsei Med. J. 55, 1214–1221 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ide, H., Inoue, S. & Miyamoto, H. Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: a meta-analysis of immunohistochemical studies. PLoS ONE 12, e0174746 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Clark, A. F., Marcellus, S., deLory, B. & Bird, C. E. Plasma testosterone free index: a better indicator of plasma androgen activity? Fertil. Steril. 26, 1001–1005 (1975).

    Article  CAS  PubMed  Google Scholar 

  63. Cheng, L. et al. Allelic loss of the active X chromosome during bladder carcinogenesis. Arch. Pathol. Lab. Med. 128, 187–190 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Fukushima, S., Hirose, M., Tsuda, H., Shirai, T. & Hirao, K. Histological classification of urinary bladder cancers in rats induced by N-butyl-n-(4-hydroxybutyl)nitrosamine. Gan 67, 81–90 (1976).

    CAS  PubMed  Google Scholar 

  65. Fantini, D. et al. A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer. Oncogene 37, 1911–1925 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shin, K. et al. Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma. Nat. Cell Biol. 16, 469–478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bertram, J. S. & Craig, A. W. Induction of bladder tumours in mice with dibutylnitrosamine. Br. J. Cancer 24, 352–359 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Imada, S. et al. Promoting effects and mechanisms of action of androgen in bladder carcinogenesis in male rats. Eur. Urol. 31, 360–364 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Okajima, E., Hiramatsu, T., Iriya, K., Ijuin, M. & Matsushima, S. Effects of sex hormones on development of urinary bladder tumours in rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. Urol. Res. 3, 73–79 (1975).

    Article  CAS  PubMed  Google Scholar 

  70. Wright, A. S., Thomas, L. N., Douglas, R. C., Lazier, C. B. & Rittmaster, R. S. Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat. J. Clin. Invest. 98, 2558–2563 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ide, H. et al. Compound A inhibits urothelial tumorigenesis via both the androgen receptor and glucocorticoid receptor signaling pathways. Am. J. Transl. Res. 12, 1779–1788 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kawahara, T. et al. Enzalutamide as an androgen receptor inhibitor prevents urothelial tumorigenesis. Am. J. Cancer Res. 7, 2041–2050 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ide, H. et al. FOXO1 as a tumor suppressor inactivated via AR/ERβ signals in urothelial cells. Endocr. Relat. Cancer 27, 231–244 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Izumi, K., Zheng, Y., Hsu, J. W., Chang, C. & Miyamoto, H. Androgen receptor signals regulate UDP-glucuronosyltransferases in the urinary bladder: a potential mechanism of androgen-induced bladder carcinogenesis. Mol. Carcinog. 52, 94–102 (2013).

    Article  PubMed  Google Scholar 

  75. Li, Y. et al. GATA3 in the urinary bladder: suppression of neoplastic transformation and down-regulation by androgens. Am. J. Cancer Res. 4, 461–473 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. Altevogt, P., Sammar, M., Hüser, L. & Kristiansen, G. Novel insights into the function of CD24: a driving force in cancer. Int. J. Cancer 148, 546–559 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Inoue, S. et al. Nuclear factor-κB promotes urothelial tumorigenesis and cancer progression via cooperation with androgen receptor signaling. Mol. Cancer Ther. 17, 1303–1314 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Markle, J. G. & Fish, E. N. SeXX matters in immunity. Trends Immunol. 35, 97–104 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Schafer, J. M. et al. Sex-biased adaptive immune regulation in cancer development and therapy. iScience 25, 104717 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  81. Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209–223 (2022).

    Article  CAS  PubMed  Google Scholar 

  82. Guan, X. et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature https://doi.org/10.1038/s41586-022-04522-6 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kwon, H. et al. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Sci. Immunol. https://doi.org/10.1126/sciimmunol.abq2630 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Yang, C. et al. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor. Immunity 55, 1268–1283.e9 (2022).

    Article  CAS  PubMed  Google Scholar 

  85. St Paul, M. & Ohashi, P. S. The roles of CD8+ T cell subsets in antitumor immunity. Trends Cell Biol. 30, 695–704 (2020).

    Article  Google Scholar 

  86. Oh, D. Y. et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625.e1613 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sato, Y. et al. CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade. JCI Insight https://doi.org/10.1172/jci.insight.121062 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Shiota, M. et al. Secondary bladder cancer after anticancer therapy for prostate cancer: reduced comorbidity after androgen-deprivation therapy. Oncotarget 6, 14710–14719 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Morales, E. E. et al. Finasteride reduces risk of bladder cancer in a large prospective screening study. Eur. Urol. 69, 407–410 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Sathianathen, N. J., Fan, Y., Jarosek, S. L., Lawrentschuk, N. L. & Konety, B. R. Finasteride does not prevent bladder cancer: a secondary analysis of the Medical Therapy for Prostatic Symptoms Study. Urol. Oncol. 36, 338.e13–338.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Moschini, M. et al. The effect of androgen deprivation treatment on subsequent risk of bladder cancer diagnosis in male patients treated for prostate cancer. World J. Urol. 37, 1127–1135 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Shiota, M. et al. Androgen receptor signaling regulates cell growth and vulnerability to doxorubicin in bladder cancer. J. Urol. 188, 276–286 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Williams, E. M., Higgins, J. P., Sangoi, A. R., McKenney, J. K. & Troxell, M. L. Androgen receptor immunohistochemistry in genitourinary neoplasms. Int. Urol. Nephrol. 47, 81–85 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Sottnik, J. L. & Theodorescu, D. CD44: a metastasis driver and therapeutic target. Oncoscience 3, 320–321 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Sottnik, J. L. et al. Androgen receptor regulates CD44 expression in bladder cancer. Cancer Res. 81, 2833–2846 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zheng, Y., Izumi, K., Yao, J. L. & Miyamoto, H. Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells. Endocr. Relat. Cancer 18, 451–464 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Boorjian, S. A. et al. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder. Endocr. Relat. Cancer 16, 123–137 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Sanguedolce, F. et al. Role of androgen receptor expression in non-muscle-invasive bladder cancer: a systematic review and meta-analysis. Histol. Histopathol. 35, 423–432 (2020).

    CAS  PubMed  Google Scholar 

  99. Luna-Velez, M. V. et al. Androgen receptor signalling confers clonogenic and migratory advantages in urothelial cell carcinoma of the bladder. Mol. Oncol. 15, 1882–1900 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wu, J. T., Han, B. M., Yu, S. Q., Wang, H. P. & Xia, S. J. Androgen receptor is a potential therapeutic target for bladder cancer. Urology 75, 820–827 (2010).

    Article  PubMed  Google Scholar 

  101. Jitao, W. et al. Androgen receptor inducing bladder cancer progression by promoting an epithelial-mesenchymal transition. Andrologia 46, 1128–1133 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Johnson, A. M. et al. Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1. BMC Urol. 8, 7 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Smith, S. C. et al. The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. Cancer Res. 66, 1917–1922 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xiao, Y. & Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 221, 107753 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Tao, L. et al. Infiltrating T cells promote bladder cancer progression via increasing IL1→Androgen Receptor→HIF1α→VEGFa signals. Mol. Cancer Ther. 15, 1943–1951 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ou, Z. et al. Tumor microenvironment B cells increase bladder cancer metastasis via modulation of the IL-8/androgen receptor (AR)/MMPs signals. Oncotarget 6, 26065–26078 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lin, C., Lin, W., Yeh, S., Li, L. & Chang, C. Infiltrating neutrophils increase bladder cancer cell invasion via modulation of androgen receptor (AR)/MMP13 signals. Oncotarget 6, 43081–43089 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Izumi, K. et al. Androgen deprivation therapy prevents bladder cancer recurrence. Oncotarget 5, 12665–12674 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Shiota, M. et al. Suppressed recurrent bladder cancer after androgen suppression with androgen deprivation therapy or 5α-reductase inhibitor. J. Urol. 197, 308–313 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Creta, M. et al. Inhibition of androgen signalling improves the outcomes of therapies for bladder cancer: results from a systematic review of preclinical and clinical evidence and meta-analysis of clinical studies. Diagnostics https://doi.org/10.3390/diagnostics11020351 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kourbanhoussen, K. et al. Switching cancers: a systematic review assessing the role of androgen suppressive therapy in bladder cancer. Eur. Urol. Focus. 7, 1044–1051 (2021).

    Article  PubMed  Google Scholar 

  114. Yasui, M. et al. Androgen receptor mRNA expression is a predictor for recurrence-free survival in non-muscle invasive bladder cancer. BMC Cancer 19, 331 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Yonekura, S., Terauchi, F., Hoshi, K., Yamaguchi, T. & Kawai, S. Androgen receptor predicts first and multiple recurrences in non-muscle invasive urothelial carcinoma of the bladder. Pathol. Oncol. Res. 25, 987–994 (2019).

    Article  CAS  PubMed  Google Scholar 

  116. Izumi, K. et al. Expression of androgen receptor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence. Oncotarget 7, 14153–14160 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02605863 (2018).

  118. Chen, J. et al. Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling. Oncogene 39, 574–586 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Anastasiadou, E., Jacob, L. S. & Slack, F. J. Non-coding RNA networks in cancer. Nat. Rev. Cancer 18, 5–18 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Goodall, G. J. & Wickramasinghe, V. O. RNA in cancer. Nat. Rev. Cancer 21, 22–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  121. Beermann, J., Piccoli, M. T., Viereck, J. & Thum, T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol. Rev. 96, 1297–1325 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Luo, Q. et al. Vasculogenic mimicry in carcinogenesis and clinical applications. J. Hematol. Oncol. 13, 19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Guo, J., Hu, J., Cao, R., Chen, Q. & Li, K. Androgen receptor is inactivated and degraded in bladder cancer cells by phenyl glucosamine via miR-449a restoration. Med. Sci. Monit. 24, 2294–2301 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Flippot, R., Beinse, G., Boilève, A., Vibert, J. & Malouf, G. G. Long non-coding RNAs in genitourinary malignancies: a whole new world. Nat. Rev. Urol. 16, 484–504 (2019).

    Article  PubMed  Google Scholar 

  125. Ogawa, Y., Sun, B. K. & Lee, J. T. Intersection of the RNA interference and X-inactivation pathways. Science 320, 1336–1341 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chen, L. & Shan, G. CircRNA in cancer: fundamental mechanism and clinical potential. Cancer Lett. 505, 49–57 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Deng, G. et al. Targeting androgen receptor (AR) with antiandrogen enzalutamide increases prostate cancer cell invasion yet decreases bladder cancer cell invasion via differentially altering the AR/circRNA-ARC1/miR-125b-2-3p or miR-4736/PPARγ/MMP-9 signals. Cell Death Differ. 28, 2145–2159 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kashiwagi, E. et al. Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer. Oncotarget 7, 49169–49179 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Tripathi, A. & Gupta, S. Androgen receptor in bladder cancer: a promising therapeutic target. Asian J. Urol. 7, 284–290 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lotan, Y. et al. Patients with muscle-invasive bladder cancer with nonluminal subtype derive greatest benefit from platinum based neoadjuvant chemotherapy. J. Urol. 207, 541–550 (2022).

    Article  PubMed  Google Scholar 

  131. de Jong, J. J. et al. Distribution of molecular subtypes in muscle-invasive bladder cancer is driven by sex-specific differences. Eur. Urol. Oncol. 3, 420–423 (2020).

    Article  PubMed  Google Scholar 

  132. Kameyama, K. et al. Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression. Int. J. Oncol. 50, 75–84 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Lee, K. H. et al. Histone demethylase KDM7A regulates androgen receptor activity, and its chemical inhibitor TC-E 5002 overcomes cisplatin-resistance in bladder cancer cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21165658 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Tyagi, A. et al. Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder. Urol. Oncol. 37, 492–502 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Huang, C. P. et al. ASC-J9® increases the bladder cancer chemotherapy efficacy via altering the androgen receptor (AR) and NF-κB survival signals. J. Exp. Clin. Cancer Res. 38, 275 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  136. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02300610 (2019).

  137. Kawahara, T. et al. ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression. Oncotarget 6, 29860–29876 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Kawahara, T. et al. Silodosin inhibits the growth of bladder cancer cells and enhances the cytotoxic activity of cisplatin via ELK1 inactivation. Am. J. Cancer Res. 5, 2959–2968 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Jiang, G. et al. Identification of BXDC2 as a key downstream effector of the androgen receptor in modulating cisplatin sensitivity in bladder cancer. Cancers https://doi.org/10.3390/cancers13050975 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Teramoto, Y. et al. Androgen receptor signaling induces cisplatin resistance via down-regulating GULP1 expression in bladder cancer. Int. J. Mol. Sci. https://doi.org/10.3390/ijms221810030 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ide, H. et al. FOXO1 inactivation induces cisplatin resistance in bladder cancer. Cancer Sci. 111, 3397–3400 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. McElree, I. M. et al. Sequential intravesical gemcitabine and docetaxel for bacillus Calmette-Guérin-naïve high-risk nonmuscle-invasive bladder cancer. J. Urol. 208, 589–599 (2022).

    Article  PubMed  Google Scholar 

  143. Balar, A. V. et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 22, 919–930 (2021).

    Article  CAS  PubMed  Google Scholar 

  144. Packiam, V. T. et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol. Oncol. 36, 440–447 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05327647 (2023).

  146. Chamie, K. et al. Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients. J. Clin. Oncol. 39, 510–510 (2021).

    Article  Google Scholar 

  147. Han, J., Gu, X., Li, Y. & Wu, Q. Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect. Biomed. Pharmacother. 129, 110393 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. van Puffelen, J. H. et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat. Rev. Urol. 17, 513–525 (2020).

    Article  PubMed  Google Scholar 

  149. Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl. Med. 4, 137ra172 (2012).

    Article  Google Scholar 

  150. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jones, S. A. & Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol. 18, 773–789 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Zhang, G. J. et al. Autocrine IL-6 production by human transitional carcinoma cells upregulates expression of the α5β1 fibronectin receptor. J. Urol. 163, 1553–1559 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Chen, F., Langenstroer, P., Zhang, G., Iwamoto, Y. & See, W. Androgen dependent regulation of bacillus Calmette-Guerin induced interleukin-6 expression in human transitional carcinoma cell lines. J. Urol. 170, 2009–2013 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. Shang, Z. et al. Antiandrogen therapy with hydroxyflutamide or androgen receptor degradation enhancer ASC-J9 enhances BCG efficacy to better suppress bladder cancer progression. Mol. Cancer Ther. 14, 2586–2594 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Luo, Y., Yamada, H., Evanoff, D. P. & Chen, X. Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells. Clin. Exp. Immunol. 146, 181–188 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Mizushima, T. et al. Androgen receptor signaling reduces the efficacy of bacillus Calmette-Guérin therapy for bladder cancer via modulating Rab27b-induced exocytosis. Mol. Cancer Ther. 19, 1930–1942 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Necchi, A. et al. Association of androgen receptor expression on tumor cells and PD-L1 expression in muscle-invasive and metastatic urothelial carcinoma: insights for clinical research. Clin. Genitourin. Cancer 16, e403–e410 (2018).

    Article  PubMed  Google Scholar 

  159. Toren, P. et al. Androgen receptor and immune cell PD-L1 expression in bladder tumors predicts disease recurrence and survival. World J. Urol. 39, 1549–1558 (2021).

    Article  CAS  PubMed  Google Scholar 

  160. Liu, Q. et al. Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling. Cancer Gene Ther. https://doi.org/10.1038/s41417-022-00506-w (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Jiang, G. et al. Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma. Aging 12, 11466–11484 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. O’Connell, T. J. et al. Androgen activity is associated with PD-L1 downregulation in thyroid cancer. Front. Cell Dev. Biol. 9, 663130 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the George Whipple Professorship, the National Natural Science Foundation of China (81902592, 82070785), Hunan Natural Science Foundation (2020JJ5884) and Hunan Province Young talents Program (2021RC3027). The authors thank K. Wolf for help with the manuscript preparation.

Author information

Author notes

  1. These authors contributed equally: Jinbo Chen, Chi-Ping Huang.

Authors and Affiliations

  1. Department of Urology, Xiangya Hospital, Central South University, Changsha, China

    Jinbo Chen, Chao Quan, Xiongbing Zu & Zhenyu Ou

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Jinbo Chen, Xiongbing Zu & Zhenyu Ou

  3. Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA

    Jinbo Chen, Zhenyu Ou, Yu-Chieh Tsai, Edward Messing, Shuyuan Yeh & Chawnshang Chang

  4. Department of Urology, China Medical University Hospital, Taichung, Taiwan

    Chi-Ping Huang & Chawnshang Chang

Authors
  1. Jinbo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chi-Ping Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiongbing Zu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenyu Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Chieh Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward Messing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuyuan Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chawnshang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiongbing Zu or Chawnshang Chang.

Ethics declarations

Competing interests

ASC-J9 was patented by the University of Rochester, the University of North Carolina and AndroScience, and then licensed to AndroScience. Both the University of Rochester and C.C. own royalties and equity in AndroScience. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Vinata Lokeshwar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Huang, CP., Quan, C. et al. The androgen receptor in bladder cancer. Nat Rev Urol 20, 560–574 (2023). https://doi.org/10.1038/s41585-023-00761-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-023-00761-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer