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
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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Research Article

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

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 3

RB depletion enables bypass of hormonal therapy.

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RB depletion enables bypass of hormonal therapy. (A) Immunoblot for RB i...
(A) Immunoblot for RB in shCon1 and shRB1 cells. Relative tumor volume of xenografts after castration is also shown. Hosts were castrated when tumors reached 100–150 mm3 (day 0). Data plotted are mean tumor size ± SD for each cohort. n = 10 (shCon1); 7 (shRB1). (B) Tumor mass at sacrifice (day 28). Individual data points represent the tumor mass of each xenograft at sacrifice, and the mean for each cohort is represented by a horizontal bar. (C) Relative serum PSA for 4 weeks after castration, beginning at the nadir (day 7 after castration, set to 1). (D) Serum PSA doubling time for each cohort was determined as follows: time (days) × loge (2)/[loge (PSA28) – loge (PSA7)], where PSA7 and PSA28 represent PSA levels at days 7 and 28 after castration. n = 9 (shCon1); 7 (shRB1). (E) Intratumor PSA mRNA levels in xenograft tissues at sacrifice were determined via qPCR. PSA relative to 18S is plotted; expression in shCon1 was set to 1. n = 5 (shCon1); 7 (shRB1). (F) PSA and TMPRSS2 mRNA levels were determined by qPCR in cells cultured for 48 hours in androgen-free (CDT) or androgen-containing (FBS) media and supplemented as indicated. Results are plotted for each treatment condition relative to that in shCon1 cells after androgen ablation (set to 1). Data reflect triplicate analyses of at least 2–3 independent biological replicates (mean ± SD). *P < 0.05, Student’s t test. See also Supplemental Figures 1 and 2.