Journal
JOURNAL OF CELL SCIENCE
Volume 120, Issue 20, Pages 3700-3712Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03484
Keywords
alpha 6 beta 4 integrin; Rac; Pak1; NF-kappa B; apoptosis resistance; mammary epithelial cells
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Funding
- NCI NIH HHS [CA 117884, CA078731] Funding Source: Medline
- NIGMS NIH HHS [GM-57388] Funding Source: Medline
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Malignant transformation and multidrug resistance are linked to resistance to apoptosis, yet the molecular mechanisms that mediate tumor survival remain poorly understood. Because the stroma can influence tumor behavior by regulating the tissue phenotype, we explored the role of extracellular matrix signaling and tissue organization in epithelial survival. We report that elevated (alpha 6) beta 4 integrin-dependent Rac-Pak1 signaling supports resistance to apoptosis in mammary acini by permitting stress-dependent activation of the p65 subunit of NF-kappa B through Pak1. We found that inhibiting Pak1 through expression of N17Rac or PID compromises NF-kappa B activation and renders mammary acini sensitive to death, but that resistance to apoptosis could be restored to these structures by overexpressing wild-type NF-kappa B p65. We also observed that acini expressing elevated levels of Pak1 can activate p65 and survive death treatments, even in the absence of activated Rac, yet will die if activation of NF-kappa B is simultaneously inhibited through expression of I kappa B alpha M. Thus, mammary tissues can resist apoptotic stimuli by activating NF-kappa B through alpha 6 beta 4 integrin-dependent Rac-Pak1 signaling. Our data emphasize the importance of the extracellular matrix stroma in tissue survival and suggest that alpha 6 beta 4 integrin-dependent Rac stimulation of Pak1 could be an important mechanism mediating apoptosis-resistance in some breast tumors.
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