ACTIVE SIGNALING BY NEU IN TRANSGENIC MICE

Transgenic mice engineered to overexpress the HER-2/neu/erbB-2 protoon cogene under the control of a mammary-specific promoter develop mammar y tumors and are a model for human breast cancer. Signal transduction by Neu was examined in situ in the tumors of these transgenic mice. Th is was accomplished using the PN2A monoclonal antibody, which recogniz es Neu only in the phosphorylated, and therefore actively signaling, s tate. Immunohistochemistry using PN2A demonstrated that Neu actively s ignals in the tumors of Neu transgenic mice. Expression of Neu was alw ays accompanied by co-overexpression of the endogenous epidermal growt h factor receptor. Qualitatively similar results were found in mammary tumors from mice bitransgenic for the neu and transforming growth fac tor-alpha genes (both driven by the mouse mammary tumor virus promoter ). Early mammary lesions demonstrated distinctive patterns of Neu acti vation relative to expression levels. Overexpression and activation we re separable both temporally and spatially. These results refine the m ulti-step model for the role of Neu in mammary neoplasia and establish phosphorylation-state specific antibodies as a powerful tool for inve stigating tumor progression.