| First Author | Yoshioka T | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 2 | Pages | 682-99 |
| PubMed ID | 23348745 | Mgi Jnum | J:194482 |
| Mgi Id | MGI:5473926 | Doi | 10.1172/JCI60720 |
| Citation | Yoshioka T, et al. (2013) beta4 Integrin signaling induces expansion of prostate tumor progenitors. J Clin Invest 123(2):682-99 |
| abstractText | The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the beta4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of beta4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective beta4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant beta4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that beta4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the beta4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells. |
