G-protein-mediated epidermal growth factor signal transduction in a human breast cancer cell line. Evidence for two intracellular pathways distinguishable by pertussis toxin.
The MDA-468 human breast cancer cell line has an amplified epidermal growth factor (EGF) receptor gene (20 x) and correspondingly overexpresses the EGF receptor. Since this cell line is growth inhibited by supra-physiological levels of EGF in tissue culture, it has been possible to select variant cells which have lost the chromosome bearing the amplified EGF receptor domain and which are capable of growing in high levels of EGF. One such cell line (MDA-468-S4) shows an absolute requirement for EGF for growth in anchorage-independent tissue culture conditions. We have utilized MDA-468 and MDA-468-S4 to examine the intracellular transduction of EGF signals leading to growth inhibition and proliferation, respectively. We report that in anchorage-independent conditions, pertussis toxin can abrogate both the EGF-dependent growth inhibition in MDA-468 cells and the EGF-dependent cell proliferation in MDA-468-S4 cells. This inhibition is paralleled by the ADP-ribosylation of an endogenous 41,000-dalton membrane protein in both MDA-468 and MDA-468-S4 cells. In contrast, the toxin does not prevent the transient, augmented expression of c-myc and c-fos mRNA seen in response to EGF in both cell types. These data suggest 1) the notion of more than one simultaneous, parallel, intracellular EGF-dependent signal transduction pathway and 2) G-protein involvement in at least one pathway mandatory for the growth modulating responses to EGF in anchorage-independent conditions, but distinct from that inducing c-myc and c-fos mRNA expression.
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D001345:Autoradiography; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009857:Oncogenes; D037342:Pertussis Toxin; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D004815:Epidermal Growth Factor; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins