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"
Altmetric Score
MSK Authors
  1. Charles L Sawyers
    157 Sawyers
  2. Jaya M Satagopan
    137 Satagopan
  3. Peter T Scardino
    621 Scardino
  4. Yu Chen
    68 Chen
  5. Jason A Koutcher
    236 Koutcher
  6. Young-Mi Kim
    3 Kim
  7. Brett Stewart Carver
    109 Carver
  8. Victor Reuter
    922 Reuter
  9. Javier A Otero
    7 Otero
  10. Howard Scher
    834 Scher