Advanced prostate cancer (PC) is characterized by incurable castration-resistant progression and osteoblastic bone metastasis.
While androgen deprivation therapy remains the primary treatment for advanced PC, resistance inevitably develops. Importantly, mounting evidence indicates that androgen receptor (AR) signaling continues to play a critical role in the growth of advanced PC despite androgen deprivation. While the mechanisms of aberrant AR activation in advanced PC have been extensively studied, the downstream AR target genes involved in progression of castration-resistance are largely unknown. Here, we identify WNT7B as a direct AR target gene highly expressed in castration-resistant prostate cancer (CRPC) cells. Our results demonstrate that expression of WNT7B is necessary for the growth of PC cells and that this effect is enhanced under androgen-deprived conditions. Further analyses reveal that WNT7B promotes androgen-independent growth of CRPC cells likely through activation of protein kinase C isozymes. Our results also show that PC-produced WNT7B induces osteoblast differentiation in vitro through a direct cell-cell interaction, and that WNT7B is upregulated in human PC xenografts that cause an osteoblastic reaction when grown in bone. Taken together, these results suggest that AR-regulated WNT7B signaling is critical for the growth of CRPC and development of the osteoblastic bone response characteristic of advanced PC.
Written by:
Zheng D, Decker KF, Zhou T, Chen J, Qi Z, Jacobs K, Weilbaecher KN, Corey E, Long F, Jia L. Are you the author?
Washington University School of Medicine.
Reference: Mol Cancer Res. 2013 Feb 5. Epub ahead of print.
doi: 10.1158/1541-7786.MCR-12-0520
PubMed Abstract
PMID: 23386686
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