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First published online 2 October 2007
doi: 10.1242/jcs.03484

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64 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-B-dependent resistance to apoptosis in 3D mammary acini

Julie C. Friedland^1,2,3,*, Johnathon N. Lakins^2,3,4,5, Marcelo G. Kazanietz¹, Jonathan Chernoff⁶, David Boettiger⁷ and Valerie M. Weaver^2,3,4,5,

¹ Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
² Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
³ Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA
⁴ Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA
⁵ Center for Bioengineering and Tissue Regeneration, University of California San Franisco, San Francisco, CA 94143, USA
⁶ Fox Chase Cancer Center, Philadelphia, PA 19111, USA
⁷ Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA

Author for correspondence (e-mail: weaverv{at}surgery.ucsf.edu)

Accepted 4 July 2007

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 (6)4 integrin-dependent Rac-Pak1 signaling supports resistance to apoptosis in mammary acini by permitting stress-dependent activation of the p65 subunit of NF-B through Pak1. We found that inhibiting Pak1 through expression of N17Rac or PID compromises NF-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-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-B is simultaneously inhibited through expression of IBM. Thus, mammary tissues can resist apoptotic stimuli by activating NF-B through 64 integrin-dependent Rac-Pak1 signaling. Our data emphasize the importance of the extracellular matrix stroma in tissue survival and suggest that 64 integrin-dependent Rac stimulation of Pak1 could be an important mechanism mediating apoptosis-resistance in some breast tumors.

Key words: 64 integrin, Rac, Pak1, NF-B, Apoptosis resistance, Mammary epithelial cells

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