Accession Number : ADA329002

Title :   Investigations of Functional and Structural Interactions Between c-src and HER2: Involvement in Human Breast Tumor Formation

Descriptive Note : Annual rept. 1 Jul 96-30 Jun 97

Corporate Author : VIRGINIA UNIV CHARLOTTESVILLE

Personal Author(s) : Belsches, Allison P. ; Parsons, Sarah J.

PDF Url : ADA329002

Report Date : JUL 1997

Pagination or Media Count : 26

Abstract : 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, C3H10T1/2, 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 HER1/c-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 and/or 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 HER2/c-Src heterocomplexes. In 3 of 13 tumor tissues, and in 3 of 9 human breast tumor cell lines, constitutive in vivo HER2/c-Src complexes were seen, suggesting structural and functional interactions between HER2 and c-Src. C3H10T1/2 fibroblast cell lines overexpressing HER2 and/or c-Src have been generated and will be tested for growth properties, heterocomplex formation and downstream signaling. Preliminary results indicate a HER2/c-Src complex in a cell line which overexpressed both kinases; no complex is seen in a cell line expressing c-Src alone.

Descriptors :   *PATIENTS, *TYROSINE, *PHOSPHORUS TRANSFERASES, *BREAST CANCER, TISSUES(BIOLOGY), HUMANS, INTERACTIONS, PROTEINS, NEOPLASMS, MUTATIONS, CLONES, FIBROBLASTS, CELLS(BIOLOGY), MAMMARY GLANDS, PHOSPHORYLATION.

Subject Categories : Biochemistry
      Genetic Engineering and Molecular Biology
      Medicine and Medical Research

Distribution Statement : APPROVED FOR PUBLIC RELEASE