Associations of ErbB2, beta1-integrin and lipid rafts on Herceptin (Trastuzumab) resistant and sensitive tumor cell lines.
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 beta1-integrins and ErbB2, as well as their association with lipid rafts. A weak functional interaction between ErbB2 and beta1-integrin and the fact that ErbB2 did not co-patch with beta1-integrins upon crosslinking imply that ErbB2 and beta1-integrin define two distinct molecular association clusters from a functional point of view. Although Herceptin-sensitive cell lines expressed more ErbB2 and fewer beta1-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 beta1-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.
Mocanu
Maria-Magdalena
MM
Department of Biophysics and Cell Biology, Research Center for Molecular Medicine, Faculty of Medicine, Medical and Health Science Center, University of Debrecen, P.O. Box 39, Nagyerdei krt. 98, H-4012 Debrecen, Hungary.
Fazekas
Zsolt
Z
Petrás
Miklós
M
Nagy
Péter
P
Sebestyén
Zsolt
Z
Isola
Jorma
J
Tímár
József
J
Park
John W
JW
Vereb
György
G
Szöllosi
János
J
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019012:Integrin beta1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab