24. Muller, W.J., C..L. Arteaga, S.K. Muthuswamy, P.M. Siegel, M.A. Webster, R.D. Cardiff, K.S. Meise, F. Li, S.A. Halter and R. Coffey. Synergistic interaction of the Neu protooncogene and TGFa in the mammary epithelium of transgenic mice. Molecular and Cellular Biology. 16:5726-5736, 1996.
(ABSTRACT)(ILLUSTRATIONS)
Abstract
Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-a) 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-a, we examined whether coexpression of TGF-a 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-a or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-a and neu in the mammary epithelium. Female mice coexpressing TGF-a 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 analysis 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-a cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.
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Last Updated: November 27, 1996
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