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  • Original Paper
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Src family kinases and HER2 interactions in human breast cancer cell growth and survival

Abstract

Evidence from murine fibroblast models and human breast cancer cells indicates that c-Src and human EGF receptor (HER1) synergize to enhance neoplastic growth of mammary epithelial cells. To investigate whether interactions between c-Src and other HER family members may also play a role in breast tumor progression, we characterized 13 human breast carcinoma cell lines and 13 tumor samples for expression of HER family members and c-Src and examined a subset of the cell lines for Src-dependent, heregulin (HRG)-augmented, anchorage-dependent and independent growth. By immunoblotting, we found that all cell lines overexpressed one or more HER family member, and 60% overexpressed c-Src. Seventy-five per cent of the tumor tissues overexpressed HER2, while 64% overexpressed c-Src. Colony formation in soft agar was enhanced by HRG in three of five cell lines tested, a response that correlated with the presence of a c-Src/HER2 heterocomplex. This result suggests that HRG may act through both HER2 and c-Src to facilitate anchorage-independent growth. In contrast, HRG had little effect on anchorage-dependent growth in any of the cell lines tested. PP1, a Src family kinase inhibitor, reduced or ablated HRG-dependent and independent soft agar growth or anchorage dependent growth, and triggered apoptosis in all cell lines tested. The apoptotic effect of PP1 could be partially or completely reversed by HRG, depending on the cell line. These results suggest that while Src family kinases may cooperate with HRG to promote the survival and growth of human breast tumor cells, they also function independently of HER2/HRG in these processes.

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Acknowledgements

The authors thank Dr S Ethier of the University of Michigan and A Ingram from the University of Virginia Tissue Procurement Facility for tumor tissue, and members of the T Parsons, M Weber, and S Parsons laboratories for their critical evaluation of this work. These studies were supported by grants CA71449 of the NIH and 4621 of the Council for Tobacco Research, awarded to SJ Parsons. AP Belsches-Jablonski and JS Biscardi were recipients of post-doctoral fellowships (DAMD 17-96-6098 and DAMD 17-97-7329, respectively), and DA Tice is a past recipient of a pre-doctoral fellowship (DAMD 17-96-6126), all from the Army Breast Cancer Initiative, D.O.D.

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Belsches-Jablonski, A., Biscardi, J., Peavy, D. et al. Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene 20, 1465–1475 (2001). https://doi.org/10.1038/sj.onc.1204205

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