Document Detail

beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.
MedLine Citation:
PMID:  12242153     Owner:  NLM     Status:  MEDLINE    
Tumor cells can evade chemotherapy by acquiring resistance to apoptosis. We investigated the molecular mechanism whereby malignant and nonmalignant mammary epithelial cells become insensitive to apoptosis. We show that regardless of growth status, formation of polarized, three-dimensional structures driven by basement membrane confers protection to apoptosis in both nonmalignant and malignant mammary epithelial cells. By contrast, irrespective of their malignant status, nonpolarized structures are sensitive to induction of apoptosis. Resistance to apoptosis requires ligation of beta4 integrins, which regulates tissue polarity, hemidesmosome formation, and NFkappaB activation. Expression of beta4 integrin that lacks the hemidesmosome targeting domain interferes with tissue polarity and NFkappaB activation and permits apoptosis. These results indicate that integrin-induced polarity may drive tumor cell resistance to apoptosis-inducing agents via effects on NFkappaB.
Valerie M Weaver; Sophie Lelièvre; Johnathon N Lakins; Micah A Chrenek; Jonathan C R Jones; Filippo Giancotti; Zena Werb; Mina J Bissell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer cell     Volume:  2     ISSN:  1535-6108     ISO Abbreviation:  Cancer Cell     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-20     Completed Date:  2003-02-27     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  101130617     Medline TA:  Cancer Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  205-16     Citation Subset:  IM    
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MeSH Terms
Apoptosis / physiology*
Basement Membrane / metabolism
Breast Neoplasms / metabolism,  pathology*
Cell Polarity
Epithelial Cells / cytology*,  metabolism
Extracellular Matrix / metabolism*,  ultrastructure
Gene Expression Regulation, Neoplastic
Integrin beta4 / metabolism*,  ultrastructure
NF-kappa B / metabolism
Tumor Cells, Cultured
Grant Support
CA 57621/CA/NCI NIH HHS; CA 64786/CA/NCI NIH HHS; CA 78731/CA/NCI NIH HHS; R01 CA057621/CA/NCI NIH HHS; R01 CA057621-07/CA/NCI NIH HHS; R01 CA064786/CA/NCI NIH HHS; R01 CA064786-05/CA/NCI NIH HHS; R01 CA078731/CA/NCI NIH HHS; R01 CA078731-02/CA/NCI NIH HHS
Reg. No./Substance:
0/Integrin beta4; 0/NF-kappa B

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