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Disruption Of Laminin-Integrin-CD151-FAK Axis Sensitizes Breast Cancer Cells To ErbB2 Antagonists

Yang, Xiuwei H. and Flores, Ludmila M. and Li, Qinglin and Zhou, Pengcheng and Xu, Fenghui and Krop, Ian E. and Hemler, Martin E. (2010) Disruption Of Laminin-Integrin-CD151-FAK Axis Sensitizes Breast Cancer Cells To ErbB2 Antagonists. Cancer Research, 70 (6). pp. 2256-2263.

Abstract

Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of
ErbB2. Knockdown of laminin-binding integrins (α6β4, α3β1) or associated tetraspanin protein CD151 reversed laminin-5 resistance, and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and FAK. Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers.

Item Type: Article
Keywords: Laminin; Integrin; Trastuzumab; ErbB2; CD151; FAK
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2344

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