Transmembrane receptor tyrosine kinases of the ErbB family play an

important role in the pathomechanism of breast tumors. We have shown that

ErbB2 forms not only molecular homoassociations, but also larger clusters

of 1000-2000 proteins in the cell membrane. These probably could be the

morphological equivalents of detergent resistant lipid domains that are

known to serve as organizing factors in transmembrane signaling. Our

project proposal is based on the hypothesis that erbB proteins in the

membrane of breast tumor cells undergo a variety of interactions with each

other and signaling molecules thereby modulating the proliferative and

metastatic properties of these cells and their response to anti-erbB2

antibody (Herceptin) therapy. We propose to map these interactions in

various breast tumor lines and clinical samples expressing members of the

ErbB family to different degrees, and sensitive or resistant to Herceptin

therapy. We expect the results to pinpoint molecular interactions, and

expression patterns of predictive value in terms of (i) the proliferative

and metastatic potential of the tumor, and (ii) its response to Herceptin

therapy and tyrosine kinase inhibitor therapy.