SYNERGISTIC INTERACTION OF THE NEU PROTOONCOGENE PRODUCT AND TRANSFORMING GROWTH-FACTOR-ALPHA IN THE MAMMARY EPITHELIUM OF TRANSGENIC MICE

Transgenic mice expressing either the neu proto-oncogene or transformi ng growth factor (TGF-alpha) in the mammary epithelium develop spontan eous focal mammary tumors that occur after a long latency, Since thr e pidermal 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 epithel ium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring e ither a mouse mammary tumor virus/TGF-alpha or a mouse mammary tumor v irus/neu transgene to generate bitransgenic mice that coexpress TGF-al pha and neu in the mammary epithelium. Female mice coexpressing TGF-al pha and neu developed multifocal mammary tumors which arose after a si gnificantly shorter latency period than either parental strain alone, The development of these mammary tumors mas correlated with the tyrosi ne phosphorylation of Neu and the recruitment of c-Src to the Neu comp lex, Immunoprecipitation and immunoblot analyses with EGFR- and Neu-sp ecific antisera, however, failed to detect physical complexes of these two receptors, Taken together, these observations suggest that Neu an d TGF-alpha cooperate in mammary tumorigenesis through a mechanism inv olving Neu and EGFR transactivation.