title: 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.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.forename: Wen-Shuz
authors.initials: WS
authors.lastname: Yeow
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Nigel
authors.initials: N
authors.lastname: Clegg
authors.forename: Chellappagounder
authors.initials: C
authors.lastname: Thangavel
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: Clay E S
authors.initials: CE
authors.lastname: Comstock
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Leonard
authors.initials: L
authors.lastname: Gomella
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000502:physiology; D016161:Genes, Retinoblastoma; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011944:Receptors, Androgen