TY - JOUR
T1 - Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists
AU - Yang, Xiuwei H.
AU - Flores, Ludmila M.
AU - Li, Qinglin
AU - Zhou, Pengcheng
AU - Xu, Fenghui
AU - Krop, Ian E.
AU - Hemler, Martin E.
PY - 2010/3/15
Y1 - 2010/3/15
N2 - 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 focal adhesion kinase (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.
AB - 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 focal adhesion kinase (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.
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UR - http://www.scopus.com/inward/citedby.url?scp=77950257304&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-4032
DO - 10.1158/0008-5472.CAN-09-4032
M3 - Article
C2 - 20197472
AN - SCOPUS:77950257304
SN - 0008-5472
VL - 70
SP - 2256
EP - 2263
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -
