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

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

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5013-5026
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number11
DOIs
Publication statusPublished - 2014 Nov 3

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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