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The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression
Ankur Sharma, … , Peter S. Nelson, Karen E. Knudsen
Ankur Sharma, … , Peter S. Nelson, Karen E. Knudsen
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4478-4492. https://doi.org/10.1172/JCI44239.
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Research Article

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

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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.

Authors

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

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Figure 4

RB loss deregulates AR occupancy at target gene loci and E2F1 expression under therapeutic conditions.

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RB loss deregulates AR occupancy at target gene loci and E2F1 expression...
(A) PSA locus depicting AREs relative to the TSS is illustrated. AR occupancy and output was determined at the indicated time points after 10 nM DHT stimulation; for comparison, AR occupancy in shCon1 at 0 hours was set to 1. In parallel, PSA mRNA was quantified relative to 18S control, and expression in shCon1 at the 0-hour time point was set to 1. (B) AR occupancy in both cell types was determined using loci specific to CRPC. (C) AR occupancy was determined as in A, but after stimulation with 10 μM Bic. (D) E2F1 expression was quantified by qPCR and immunoblot in LNCaP and LAPC4 cells after RB knockdown. qPCR data in A–D represent mean ± SD of 3 replicates; similar results were obtained in at least 2 independent experiments. (E) Immunoblots for E2F1 after 48 hours of androgen ablation or under parallel conditions supplemented with 1 μM Bic. (F) Immunoblot of E2F1 from representative tumors described in Figure 3 at sacrifice. See also Supplemental Figures 3 and 4.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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