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

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 2

NCoA2 collaborates with PTEN loss to promote PCa progression and metastasis.

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NCoA2 collaborates with PTEN loss to promote PCa progression and metasta...
(A) H&E-stained sections of representative AP, DLP, and VP at 6–7 months of age in PTENPC+/– and PTENPC+/– NCoA2PCOE/+ mice. (B) The percentage of proliferating and apoptotic cells in PTENPC+/– and PTENPC+/– NCoA2PCOE/+ mice at 6 months of age were determined using Ki67 and cleaved caspase 3 assays, respectively. (C) Top: Macroscopic dissection image of prostate isolate from PTENPC+/– and PTENPC+/– NCoA2PCOE/+ mice. Representative images of luciferase-reporter activity of PTENPC+/– and PTENPC+/– NCoA2PCOE/+ mice at 12 months of age are displayed. Middle: Luciferase activity of PCa cells that have metastasized to distant sites in the chest area (exposed for 5 minutes). Bottom: Luciferase activity in the prostate and surrounding area (exposed for 1 minute). (D) H&E-stained sections of DLP at 12 months of age and IHC analyses of α-SMA and CK8 in prostate tumors. (E) Left: AR expression in lumbar lymph nodes (top) and lungs (bottom) at 12 months of age. For quantitative results of metastatic incidence, see Table 1. Right: Relative mRNA levels of Ar and Ck8 levels in lymph node from PTENPC+/– and PTENPC+/– NCoA2PCOE/+ mice (n = 6). Scale bars: 50 μm (A, D, and E). *P < 0.05; **P < 0.01.