Associations of ErbB2, ß1-integrin and lipid rafts on Herceptin® (Trastuzumab) resistant and sensitive tumor cell lines.
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Cancer Letters. 2005, 227(2):201-212.

Mocanu, M., Fazekas, Z., Petrás, M., Nagy, P., Sebestyén, Z., Isola, J., Tímár, J., Park, J. W., Vereb, G., Jr. & Szöll
ősi, J.

ErbB2-mediated transmembrane signaling is a key target of novel anticancer agents such as Herceptin. Our comparison of Herceptin resistant (JIMT-1, MKN-7) and sensitive (SKBR-3, N-87) cell lines demonstrates the importance of ErbB2 association patterns involving integrins and lipid rafts. Flow cytometric FRET and confocal microscopic measurements revealed colocalization and molecular proximity between β1-integrins and ErbB2, as well as their association with lipid rafts. A weak functional interaction between ErbB2 and β1-integrin and the fact that ErbB2 did not co-patch with β1-integrins upon crosslinking imply that ErbB2 and β1-integrin define two distinct molecular association clusters from a functional point of view. Although Herceptin-sensitive cell lines expressed more ErbB2 and fewer β1-integrin molecules on their surface than their resistant counterparts, this finding probably does not explain the Herceptin resistant phenotype due to the weak interaction between β1-integrins and ErbB2. Our results imply that the true significance of the expression profile of proteins involved in oncogenesis can only be understood after characterizing their molecular interactions.

Keywords: Receptor tyrosine kinase; ErbB; β1-integrin; Herceptin resistance; Lipid rafts; Confocal microscopy; Fluorescence resonance energy transfer

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