beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.

Titlebeta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.
Publication TypeJournal Article
Year of Publication2002
AuthorsWeaver VM, Lelièvre S, Lakins JN, Chrenek MA, Jones JCR, Giancotti F, Werb Z, Bissell MJ
JournalCancer Cell
Volume2
Issue3
Pagination205-16
Date Published2002 Sep
ISSN1535-6108
KeywordsApoptosis, Basement Membrane, Breast Neoplasms, Cell Polarity, Epithelial Cells, Extracellular Matrix, Female, Gene Expression Regulation, Neoplastic, Humans, Integrin beta4, NF-kappa B, Tumor Cells, Cultured
Abstract

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.

Alternate JournalCancer Cell
PubMed ID12242153
PubMed Central IDPMC2788997
Grant ListCA 57621 / CA / NCI NIH HHS / United States
CA 64786 / CA / NCI NIH HHS / United States
CA 78731 / CA / NCI NIH HHS / United States
R01 CA057621-07 / CA / NCI NIH HHS / United States
R01 CA064786-05 / CA / NCI NIH HHS / United States
R01 CA078731-02 / CA / NCI NIH HHS / United States