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Prolactin regulation of the prostate gland: a female player in a male game

Nature Reviews Urology volume 8, pages 597–607 (2011)Cite this article

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Abstract

Prolactin is best known for its actions on the mammary gland. However, circulating prolactin is also detected in males and its receptor (PRLR) is expressed in the prostate, suggesting that the prostate is a target of prolactin. Germline knockout of prolactin or its receptor has failed to reveal a key role for prolactin signaling in mouse prostate physiology. However, several studies involving rodent models and human prostate cell lines and specimens have supported the contribution of the canonical PRLR–Jak2–Stat5a/b pathway to prostate cancer tumorigenesis and progression. Increased expression of prolactin in the prostate itself (rather than changes in circulating prolactin levels) and crosstalk with androgen receptor (AR) signaling are potential mechanisms for increased Stat5a/b signaling in prostate cancer. In the mouse prostate, prolactin overexpression results in disorganized expansion of the basal/stem cell compartment, which has been proposed to house putative prostate tumor-initiating cells. These findings provide new insight into the molecular and cellular targets by which locally produced prolactin could contribute to prostate cancer initiation and progression. A number of pharmacological inhibitors targeting various levels of the PRLR–Jak2–Stat5a/b pathway have been developed and are entering clinical trials for advanced prostate cancer.

Key Points

  • Phenotypic analysis of prolactin or prolactin receptor (PRLR) deficient mice suggest that PRLR signaling moderately contributes to prostate development and physiology, but corresponding data for humans are currently lacking

  • Involvement of prolactin in benign prostate diseases has been proposed, based on the identification of such phenotypes in prolactin-overexpressing rodent models; however, the corresponding evidence is outstanding for humans

  • Circulating prolactin levels do not correlate with prostate cancer risk in humans; however, overactivation of PRLR signaling by increased prostatic expression of prolactin might contribute to prostate cancer progression

  • Putative tumor-initiating cells localize within the basal/stem cell compartment in the prostate epithelium—the histological phenotype of prostate tumors developed by prolactin-overexpressing mice involves disorganized amplification of this compartment

  • Stat5a/b is a primary mediator of prolactin effects in prostate epithelium; Stat5a/b is critical in prostate cancer progression, and inhibition of this pathway leads to widespread apoptosis

  • The PRLR, its associated kinase Jak2, or the transcription factor Stat5a/b offer potential targets for pharmaceutical intervention; proof-of-concept in experimental models has been obtained for various inhibitors

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Figure 1: Potential mechanisms of autocrine prolactin-induced prostate tumorigenesis.
Figure 2: PRLR signaling in prostate epithelium and current drug development strategies.

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Acknowledgements

The authors are grateful to Dr Lucila Sackmann-Sala for critical reading of this manuscript, and to Dr Nira Ben-Jonathan for helpful discussions during the revision of this manuscript. The authors are supported by grants from the Association for International Cancer Research (AICR Grant 05-0603) and NIH National Cancer Institute (Grant 1RO1CA113580-01A1).

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Authors and Affiliations

  1. Inserm, Unit 845, Research Center Growth and Signaling, Prolactin/GH Pathophysiology Laboratory, University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Necker site, Paris F-75015, France,

    Vincent Goffin & Roman L. Bogorad

  2. Kimmel Cancer Center, Thomas Jefferson University, 309A Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, 19107-5541, PA, USA

    David T. Hoang & Marja T. Nevalainen

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  1. Vincent Goffin
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  2. David T. Hoang
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  3. Roman L. Bogorad
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Contributions

V. Goffin, D. T. Hoang, and M. T. Nevalainen researched data for the article, made substantial contributions to discussions of content, wrote the article and reviewed and edited the article before submission. R. L. Bogorad researched data for the article and reviewed and edited the article before submission.

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Correspondence to Vincent Goffin.

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Goffin, V., Hoang, D., Bogorad, R. et al. Prolactin regulation of the prostate gland: a female player in a male game. Nat Rev Urol 8, 597–607 (2011). https://doi.org/10.1038/nrurol.2011.143

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