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Published 22 December 2003. doi:10.1083/jcb.200302023
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© The Rockefeller University Press, 0021-9525/2003/12/1397 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1397-1407

Article

 Autocrine laminin-5 ligates {alpha}6ß4 integrin and activates RAC and NF{kappa}B to mediate anchorage-independent survival of mammary tumors

Nastaran Zahir1,2, Johnathon N. Lakins1, Alan Russell3,4, WenYu Ming5, Chandrima Chatterjee1, Gabriela I. Rozenberg1, M. Peter Marinkovich3 and Valerie M. Weaver1,2

1 Department of Pathology and Laboratory Medicine, School of Medicine
2 Department of Bioengineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104
3 Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305
4 Department of Cell Biology, Cytokinetics, Inc., South San Francisco, CA 94080
5 Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202

Address correspondence to Valerie M. Weaver, Institute for Medicine and Engineering, University of Pennsylvania, 1170 Vagelos Research Laboratory, 3340 Smith Walk, Philadelphia, PA 19104-6383. Tel.: (215) 573-7389. Fax: (215) 573-6815. email: vmweaver{at}mail.med.upenn.edu

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express {alpha}6ß4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail–truncated {alpha}6ß4 integrin. {alpha}6ß4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of ß4 integrin is necessary for basal and epidermal growth factor–induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional ß1 and ß4 integrin through activation of NF{kappa}B, and overexpression of NF{kappa}B p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5–{alpha}6ß4 integrin–RAC–NF{kappa}B signaling.

Key Words: mammary epithelial cell; ß4 integrin; apoptosis; GTPase; microenvironment

Abbreviations used in this paper: 2D, two-dimensional; 3D, three-dimensional; ; ß4{Delta}cyto, tailless ß4 integrin; ß4WT, wild-type ß4 integrin; BM, basement membrane; LM-5, laminin 5; MEC, mammary epithelial cell; rBM, reconstituted BM.


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