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Time to stratify? The retinoblastoma protein in castrate-resistant prostate cancer

Nature Reviews Urology volume 8, pages 562–568 (2011)Cite this article

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Abstract

It is generally held that the retinoblastoma (RB) tumor suppressor functions in multiple tissues to protect against tumor development. However, preclinical studies and analysis of tumor samples of early disease did not support an important role of RB loss in the origin of prostate cancer. By contrast, recent observations in the clinical setting and subsequent modeling of RB function indicate that the tumor suppressor has specialized roles in controlling androgen receptor expression in prostate cancer, and primarily functions to prevent progression to the castration-resistant stage of disease. Furthermore, preclinical models have now shown that loss of RB expression or functional activity decreases the effectiveness of hormone therapy, yet seems to increase sensitivity to a subset of chemotherapeutic agents. Here, the current state of knowledge regarding the implications of RB loss for prostate cancer progression will be reviewed, and potential opportunities for developing RB as a metric to predict therapeutic response will be considered.

Key Points

  • The retinoblastoma (RB) tumor suppressor is frequently lost or functionally inactivated in castration-resistant prostate cancer

  • RB protects against progression to castration resistance in part through modulation of androgen receptor expression and activity

  • Xenograft models of human prostate cancer suggest that RB downregulation contributes to the emergence of the castration-resistant phenotype

  • Although RB-deficient tumors may respond poorly to hormone therapy, evidence in multiple cancer types suggest that tumors low in RB exhibit a heightened initial response to chemotherapy

  • Tumor cells deficient in RB function show tissue-specific and context-specific loss of DNA damage checkpoints

  • RB status is a candidate for development as a pharmacodynamic marker of transition to castration resistance and as a predictive marker of response to therapy that might guide therapeutic decisions

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Figure 1: RB controls prostate cancer progression.
Figure 2: A conceptual model for stratification based on RB status.

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Acknowledgements

The authors would like to thank Drs Chris Logothetis, Angelo DeMarzo, Adam Dicker, Leonard Gomella, Kevin Kelly, and Erik Knudsen, the Greater Philadelphia Prostate Cancer Working Group, and Matthew Schiewer for critical discussion and comments. We would also like to thank Ms Beth Schade for technical and artwork assistance. We regret omission of additional citations due to space constraints. The authors are supported by grants from the NIH (CA099996 and CA116777 to K. E. Knudsen), US Department of Defense (to R. B. Den), and the Prostate Cancer Foundation (to K. E. Knudsen and R. B. Den).

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Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, TX, USA

    Ana Aparicio

  2. Departments of Cancer Biology, Urology, and Radiation Oncology, Thomas Jefferson University and Kimmel Cancer Center, 233 South 10th Street, BLSB 1008A, Philadelphia, 19107, PA, USA

    Robert B. Den & Karen E. Knudsen

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All authors contributed equally to researching data, discussing the content and writing the article and performing review/editing of the manuscript before submission.

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Correspondence to Karen E. Knudsen.

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Aparicio, A., Den, R. & Knudsen, K. Time to stratify? The retinoblastoma protein in castrate-resistant prostate cancer. Nat Rev Urol 8, 562–568 (2011). https://doi.org/10.1038/nrurol.2011.107

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