β4 Integrin signaling induces expansion of prostate tumor progenitors Journal Article
| Authors: | Yoshioka, T.; Otero, J.; Chen, Y.; Kim, Y. M.; Koutcher, J. A.; Satagopan, J.; Reuter, V.; Carver, B.; de Stanchina, E.; Enomoto, K.; Greenberg, N. M.; Scardino, P. T.; Scher, H. I.; Sawyers, C. L.; Giancotti, F. G. |
| Article Title: | β4 Integrin signaling induces expansion of prostate tumor progenitors |
| Abstract: | 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 β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 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 β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 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 β4 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 β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 123 |
| Issue: | 2 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2013-01-25 |
| Start Page: | 682 |
| End Page: | 699 |
| Language: | English |
| DOI: | 10.1172/jci60720 |
| PROVIDER: | scopus |
| PMCID: | PMC3561800 |
| PUBMED: | 23348745 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 March 2013" - "CODEN: JCINA" - "Source: Scopus" |
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