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

Evidence from murine fibroblast models and human breast cancer cells indica tes that c-Src and human EGF receptor (HER1) synergize to enhance neoplasti c growth of mammary epithelial cells, To investigate whether interactions b etween c-Src and other HER members may also play a role in breast tumor pro gression, we characterized 13 human breast carcinoma cell lines and 13 tumo r samples for expression of HER family members and c-Src and examined a sub set of the cell lines for Src-dependent, heregulin (HRG)-augmented, anchora ge-dependent and independent growth. By immunoblotting, we found that all c ell lines overexpressed one or more HER family member, and 60% overexpresse d c-Src, Seventy-five per cent of the tumor tissues overexpressed HER2, whi le 64% overexpressed c-Src, Colony formation in soft agar was enhanced by H RG in three of five cell lines tested, a response that correlated,vith the presence of a c-Src/HER2 heterocomplex, This result suggests that HRG may a ct 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 ablat ed HRG-dependent and independent soft agar growth or anchorage dependent gr owth, and triggered apoptosis in all cell lines tested. The apoptotic effec t of PP1 could be partially or completely reversed by HRG, depending on the cell line. These results suggest that while Src family kinases may coopera te with HRG to promote the survival and growth of human breast tumor cells, they also function independently of HER2/HRG in these processes.