The gene encoding the neu/erbB-2/HER-2 receptor tyrosine kinase is one of a small number of genes known to be altered in human breast and ovarian carcinoma, and therefore has great potential as a prognostic indicator and therapeutic target. Efforts to exploit this receptor in the clinical arena have been impeded by the failure to consider regulation of neu by hormones and co-receptors. This has been complicated by the fact that at least seven different peptide hormones, are all able to activate neu, by binding to the co-receptors, EGF receptor, erbB-3, and erbB-4, which then dimerize with neu. Work by Dr Stern has shown that each one of the growth factors activates a different constellation of receptors, leading to a great diversity of possible responses. Moreover, the coupling of cellular responses to each factor is determined by the subset of receptors expressed in each tissue. Thus in order to interpret the function of any one of the factors or receptors, including neu, it is essential to consider the influences provided by the entire set. Both rodent and human systems will be used to develop a model for the function of neu and its regulatory hormones in mammary carcinoma. The normal pattern of expression of the entire hormone and receptor set will be profiled in endogenous mouse mammary epithelium using reverse- transcriptase-PCR, in situ hybridization, and immunohistochemistry. The next goal will be to determine the response of mouse mammary epithelium to the pertinent growth factors, using pellet implants, and to verify the results using a dominant negative transgenic system. These two aims will reveal the contribution of each hormone and each receptor to growth regulation of mouse mammary epithelium.
The third aim will be to verify that the results extrapolate to human tissue. The final goal will be to exploit a unique tool developed in this laboratory, phosphorylation- sensitive antisera directed against each of the four receptors. These sera recognize the individual receptors only when actively signaling. These results from Aims 1 and 2, should predict the combination of receptor activations linked to proliferation. This will be tested by immuno-staining mammary carcinoma specimens with phosphorylation- sensitive antibodies.
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