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Role of oestrogen receptors in bladder cancer development

Nature Reviews Urology volume 10, pages 317–326 (2013)Cite this article

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Abstract

Early studies documented the existence of sexual dimorphism in bladder cancer occurrence and progression, with a greater bladder cancer incidence in males than females. However, the progression of bladder cancer after diagnosis is much quicker in females than males. These findings can be explained by the effects of female hormones (predominantly oestrogens) and their binding receptors, including oestrogen receptor 1 (ESR1; also known as ERα), oestrogen receptor 2 (ESR2; also known as ERβ), and GPR30 protein on bladder cancer incidence and progression. Results from studies using various in vitro cell lines and in vivo mouse models demonstrate differential roles of oestrogen receptors in cancer initiation and progression. ERα suppresses bladder cancer initiation and invasion, whereas ERβ promotes bladder cancer initiation and progression. Mechanistic studies suggest that ERα and ERβ exert these effects via modulation of the AKT pathway and DNA replication complex, respectively. Targeting these signalling pathways—for example, with ERα agonists, ERβ antagonists, or selective oestrogen receptor modulators such as 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (also known as PHTPP)—could lead to the development of new therapeutic approaches for controlling bladder cancer progression.

Key Points

  • Although bladder cancer incidence is greater in men, bladder cancer tends to be more aggressive in women (greater muscle invasion rate), suggesting that oestrogen inhibits tumour initiation but promotes invasion

  • Differential expression of oestrogen receptor 1 (ESR1; also known as ERα) and oestrogen receptor 2 (ESR2; also known as ERβ) in human bladder cancers implicates different roles in bladder tumorigenesis

  • Reported inconsistencies in ERα and ERβ expression—and their correlation with bladder cancer stage, grade, and patient survival—can be explained by differences in study design and disease complexity

  • Studies of mouse models and human cell lines suggest that ERα suppresses initiation and invasion, whereas ERβ promotes initiation and progression

  • Inducible knockout mouse studies (with selective deletion of ERα, ERβ, or GPR30 in urothelial cells at specific stages of tumorigenesis) could elucidate the role of oestrogens in bladder cancer development

  • New therapeutic approaches might selectively target ERα or ERβ (or their downstream target genes); for example, a selective ERα agonist or ERβ antagonist could have therapeutic effect

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Figure 1: Differential roles of oestrogen receptors in bladder cancer development.

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Acknowledgements

The authors were partly supported in this work by the National Cancer Institute grant CA137474.

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Authors and Affiliations

  1. Department of Urology, George Whipple Lab for Cancer Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, 14642, NY, USA

    Iawen Hsu, Spencer Vitkus, Jun Da & Shuyuan Yeh

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  1. Iawen Hsu
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Contributions

I. Hsu and S. Yeh researched, wrote, edited, and discussed the article with colleagues. S. Vitkus made substantial contributions to discussions of content and reviewed the article prior to submission. J. Da researched data for the article and also made substantial contributions to discussions of content.

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Correspondence to Shuyuan Yeh.

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Hsu, I., Vitkus, S., Da, J. et al. Role of oestrogen receptors in bladder cancer development. Nat Rev Urol 10, 317–326 (2013). https://doi.org/10.1038/nrurol.2013.53

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