β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium

被引:627
作者
Weaver, VM [1 ]
Lelièvre, S
Lakins, JN
Chrenek, MA
Jones, JCR
Giancotti, F
Werb, Z
Bissell, MJ
机构
[1] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA
[2] Univ Penn, Inst Med & Engn, Philadelphia, PA 19104 USA
[3] Purdue Univ, Basic Med Sci Dept, W Lafayette, IN 47907 USA
[4] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada
[5] Northwestern Univ, Sch Med, Dept Mol & Cell Biol, Chicago, IL 60611 USA
[6] Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA
[7] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[8] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA
关键词
D O I
10.1016/S1535-6108(02)00125-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:205 / 216
页数:12
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