The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

Ankur Sharma, Wen Shuz Yeow, Adam Ertel, Ilsa Coleman, Nigel Clegg, Chellappagounder Thangavel, Colm Morrissey, Xiaotun Zhang, Clay E S Comstock, Agnieszka K. Witkiewicz, Leonard Gomella, Erik S. Knudsen, Peter S. Nelson, Karen E. Knudsen

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes.

Original languageEnglish (US)
Pages (from-to)4478-4492
Number of pages15
JournalJournal of Clinical Investigation
Volume120
Issue number12
DOIs
StatePublished - Dec 1 2010

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Retinoblastoma
Androgens
Prostatic Neoplasms
Neoplasms
Androgen Receptors
Cytoplasmic and Nuclear Receptors
E2F1 Transcription Factor
Castration
Cell Cycle Checkpoints
Prostate
Cell Cycle
Carcinogenesis
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sharma, A., Yeow, W. S., Ertel, A., Coleman, I., Clegg, N., Thangavel, C., ... Knudsen, K. E. (2010). The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. Journal of Clinical Investigation, 120(12), 4478-4492. https://doi.org/10.1172/JCI44239

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. / Sharma, Ankur; Yeow, Wen Shuz; Ertel, Adam; Coleman, Ilsa; Clegg, Nigel; Thangavel, Chellappagounder; Morrissey, Colm; Zhang, Xiaotun; Comstock, Clay E S; Witkiewicz, Agnieszka K.; Gomella, Leonard; Knudsen, Erik S.; Nelson, Peter S.; Knudsen, Karen E.

In: Journal of Clinical Investigation, Vol. 120, No. 12, 01.12.2010, p. 4478-4492.

Research output: Contribution to journalArticle

Sharma, A, Yeow, WS, Ertel, A, Coleman, I, Clegg, N, Thangavel, C, Morrissey, C, Zhang, X, Comstock, CES, Witkiewicz, AK, Gomella, L, Knudsen, ES, Nelson, PS & Knudsen, KE 2010, 'The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression', Journal of Clinical Investigation, vol. 120, no. 12, pp. 4478-4492. https://doi.org/10.1172/JCI44239
Sharma, Ankur ; Yeow, Wen Shuz ; Ertel, Adam ; Coleman, Ilsa ; Clegg, Nigel ; Thangavel, Chellappagounder ; Morrissey, Colm ; Zhang, Xiaotun ; Comstock, Clay E S ; Witkiewicz, Agnieszka K. ; Gomella, Leonard ; Knudsen, Erik S. ; Nelson, Peter S. ; Knudsen, Karen E. / The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 12. pp. 4478-4492.
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