Investigations of Functional and Structural Interactions Between c-src and HER2: Involvement in Human Breast Tumor Formation
Abstract
Overexpression of HER family members and c-Src occurs in a majority of human breast cancers, suggesting the two tyrosine kinases may cooperate during neoplastic transformation. Synergism between c-Src and HER1 in tumorigenesis has been demonstrated in a murine fibroblast model and supported by studies in human breast cancer cells. To investigate whether c-Src/HER2 interactions may also play a role in breast tumor progression, we characterized a panel of thirteen human breast carcinoma cell lines and thirteen tumor samples for expression levels of HER family members and c-Src and for the in vivo presence of c-Src/HER2 heterocomplexes. A subset of the lines were examined for their growth rates in reduced serum, their ability to form colonies in soft agar in response to heregulin (HRG) and the requirement of c-Src kinase activity in these processes. By immunoblotting, in ^90% of the cell lines and tumor tissues tested, either HER1 or HER2 was overexpressed, while c-Src was overexpressed in >70% of the samples. HRG potentiated low-serum growth in five of six cell lines tested. Colony formation in soft agar was potentiated by HRG in three of the six, but only in those cell lines which exhibited a c-Src/HER2 heterocomplex, suggesting that physical association between c-Src and HER2 promoted HRG-potentiated, anchorage-independent growth. HRG effects were either partially or completely ablated by PP1, a Src family kinase inhibitor, which induced apoptosis after long-term treatment. Partial ablation could be accounted for by an anti-apoptotic effect of HRG. Taken together, these data indicate HRG can function co-operatively with and independently of c-Src to promote survival and growth of human breast tumor cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADB239338
Entities
People
- Allison P. Belsches
Organizations
- University of Virginia