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Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer
Jun Qin, … , Sophia Y. Tsai, Ming-Jer Tsai
Jun Qin, … , Sophia Y. Tsai, Ming-Jer Tsai
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):5013-5026. https://doi.org/10.1172/JCI76412.
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Research Article Oncology

Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer

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Abstract

A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy.

Authors

Jun Qin, Hui-Ju Lee, San-Pin Wu, Shih-Chieh Lin, Rainer B. Lanz, Chad J. Creighton, Francesco J. DeMayo, Sophia Y. Tsai, Ming-Jer Tsai

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Figure 1

Oncogenic role of NCoA2 in PIN.

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Oncogenic role of NCoA2 in PIN.
(A) Scheme of conditional overexpression...
(A) Scheme of conditional overexpression of NCoA2 (ROSA26 Lox-STOP-Lox; Flag-NCoA2OE/+). (B) IF and Western blot analysis of NCoA2 overexpression in prostate epithelium from wild-type and NCoA2PCOE/+ mice at 2 months of age. (C) Top: Western blot analysis of NCoA2 expression in the prostates from wild-type and NCoA2PCOE/+ mice, immortalized prostate epithelial cells, RWPE1, and prostate cancer cells including LNCaP, LNCaP-Abl, DU145, PC3, and 22Rv1. Bottom: NCoA2 expression in NCoA2PCOE/+ and wild-type mice. (D) qRT-PCR analysis of Ncoa2 expression in the prostates from NCoA2PCOE/+ mice and the intact or castrated wild-type mice. (E) H&E-stained sections of representative anterior prostate (AP), dorsolateral prostate (DLP), and ventral prostate (VP) at 14 months of age in wild-type and NCoA2PCOE/+ mice. Arrows indicate PIN (bottom). Scale bars: 20 μm (B); 50 μm (E).

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

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