Synergistic interaction of the Neu proto-oncogene product and transforming growth factor α in the mammary epithelium of transgenic mice

William J. Muller, Carlos L. Arteaga, Senthil K. Muthuswamy, Peter M. Siegel, Marc A. Webster, Robert Cardiff, Katherine S. Meise, Feng Li, Susan A. Halter, Robert J. Coffey

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Abstract

Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-α) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a lung latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-α, we examined whether coexpression of TGF-α 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-α or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-α and neu in the mammary epithelium. Female mice coexpressing TGF-α 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-α cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

Original languageEnglish (US)
Pages (from-to)5726-5736
Number of pages11
JournalMolecular and Cellular Biology
Volume16
Issue number10
StatePublished - Sep 30 1996

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Muller, W. J., Arteaga, C. L., Muthuswamy, S. K., Siegel, P. M., Webster, M. A., Cardiff, R., Meise, K. S., Li, F., Halter, S. A., & Coffey, R. J. (1996). Synergistic interaction of the Neu proto-oncogene product and transforming growth factor α in the mammary epithelium of transgenic mice. Molecular and Cellular Biology, 16(10), 5726-5736.