title: Epidermal growth factor stimulation can substitute for c-Src overexpression in promoting breast carcinoma invasion.
abstract: OBJECTIVE
  Cancer progression is in large part dependent on the complex process of cell invasion, involving adhesion, motility, and enzymatic proteolysis. Overexpression of the Src proto-oncogene (c-Src), a nonreceptor tyrosine kinase, has been implicated in the progression of both colon and breast cancer. Our group has previously reported that overexpression of c-Src leads to a significant gain in invasive cell behavior in vitro. In this study, we sought to assess the relative importance of epidermal growth factor (EGF) stimulation and c-Src overexpression in conferring an invasive phenotype.
  
  
  METHODS
  Breast carcinoma cells and colon epithelial cells which naturally express low levels of c-Src were used for these studies. The cells were transfected so that they overexpressed c-Src; the mock-transfected parent lines were used as controls. Transfectants were tested for changes in invasion patterns after Src inhibition and EGF stimulation.
  
  
  RESULTS
  Invasion assays in both cell systems confirmed the importance of c-Src in determining invasive potential. A significant correlation was shown between c-Src kinase protein and cell invasion. Furthermore, Src inhibition significantly inhibited invasion in a dose-dependent manner. To clarify the relative contribution of EGF and c-Src to cell invasion, the ability of cells to invade through growth-factor-reduced matrigel, with or without EGF added, was compared to invasion through intact matrigel. The breast and colon cell lines behave quite differently in this regard. In the colon model, overexpressed c-Src is critical for cell invasion and stimulation with EGF is synergistic with c-Src overexpression. Conversely, the breast carcinoma cells transfected with c-Src were unable to invade without EGF stimulation and did not demonstrate the same synergistic relationship between c-Src and EGF. Instead, our results indicate that in BT474 breast carcinoma cells, EGF can substitute for c-Src in promoting breast cancer cell invasion.
  
  
  CONCLUSIONS
  Because most breast carcinomas overexpress c-Src, it behooves one to question the extent to which reducing the amount of EGF and consequent EGFR activity will decrease invasion. In this study, the effects of EGF on cell invasion were determined in light of a single alteration in c-Src expression. Our results show that EGF enhances the impact of c-Src overexpression on invasion. In breast cancer cells, EGF is capable of inducing invasion to the same extent as c-Src overexpression. This suggests that anti-EGFR therapies will be efficacious in retarding breast carcinoma invasion and metastasis.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lotz
authors.forename: Helen H-F
authors.initials: HH
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Cance
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Matthews
authors.forename: Susan
authors.initials: S
authors.lastname: Pories
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D003106:Colon / Q000166:cytology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D016391:Genes, src / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000276:immunology*; D000090063:Proto-Oncogene Mas; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004815:Epidermal Growth Factor