Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice.
Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-alpha, we examined whether coexpression of TGF-alpha and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-alpha and neu in the mammary epithelium. Female mice coexpressing TGF-alpha and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-alpha cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.
Muller
W J
WJ
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Arteaga
C L
CL
Muthuswamy
S K
SK
Siegel
P M
PM
Webster
M A
MA
Cardiff
R D
RD
Meise
K S
KS
Li
F
F
Halter
S A
SA
Coffey
R J
RJ
D000375:Aging; D000818:Animals; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D018734:Genes, erbB-2; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha