title: The steroid receptor coactivator-3 is required for the development of castration-resistant prostate cancer.
abstract: The transcriptional coactivator SRC-3 plays a key role in enhancing prostate cancer cell proliferation. Although SRC-3 is highly expressed in advanced prostate cancer, its role in castration-resistant prostate cancer (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human prostate cancer. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC-3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them with mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to noncastrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1), and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen-repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC-3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Jean C-Y
authors: JC
authors: Tien
authors: Zhaoliang
authors: Z
authors: Liu
authors: Lan
authors: L
authors: Liao
authors: Fen
authors: F
authors: Wang
authors: Yixiang
authors: Y
authors: Xu
authors: Ye-Lin
authors: YL
authors: Wu
authors: Niya
authors: N
authors: Zhou
authors: Michael
authors: M
authors: Ittmann
authors: Jianming
authors: J
authors: Xu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D011944:Receptors, Androgen; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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