Investigations of Functional and Structural Interactions Between c-src and HER2: Involvement in Human Breast Tumor Formation
Annual rept. 1 Jul 96-30 Jun 97
VIRGINIA UNIV CHARLOTTESVILLE
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Studies have shown that functional interaction between members of the human EGF receptor HER receptor tyrosine kinase family, and c-Src, a non-receptor tyrosine kinase, may be involved in breast tumor formation. We have demonstrated overexpression of HER1 and c-Src, in a murine fibroblast cell line, C3H10T12, results in an EGF-dependent synergistic increase in tumorigenicity, as compared to overexpression of either kinase alone. This increase in tumorigenicity correlates with formation of in vivo HER1c-Src complexes, the appearance of two novel phosphorylation sites on HER1, and enhanced phosphorylation of receptor substrates. HER2 is overexpressed in 20-30 of human breast cancers, and is correlated with poor patient prognosis. Also, elevated levels andor activity of c-Src have been demonstrated in human breast cancers. We propose HER1 and HER2 interact with c-Src through similar mechanisms to augment cellular growth and tumor progression. To examine potential interactions between HER2 and c-Src, we have studied human breast tumor tissue, and a panel of human breast carcinoma cell lines, for expression of HER family members and c-Src protein. Tumor samples and cell lines were also tested for HER2c-Src heterocomplexes. In 3 of 13 tumor tissues, and in 3 of 9 human breast tumor cell lines, constitutive in vivo HER2c-Src complexes were seen, suggesting structural and functional interactions between HER2 and c-Src. C3H10T12 fibroblast cell lines overexpressing HER2 andor c-Src have been generated and will be tested for growth properties, heterocomplex formation and downstream signaling. Preliminary results indicate a HER2c-Src complex in a cell line which overexpressed both kinases no complex is seen in a cell line expressing c-Src alone.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research