NDF HEREGULIN INDUCES PERSISTENCE OF TERMINAL END BUDS AND ADENOCARCINOMAS IN THE MAMMARY-GLANDS OF TRANSGENIC MICE/

Neu differentiation factor (NDF), a member of the neuregulin family of ligands of erbB receptors, induces both differentiative and mitogenic effects on cultured human mammary epithelial cells, Since members of the epidermal growth factor receptor family, including Neu/erbB2, have been implicated in mammary carcinoma, we wished to know whether a pot ential ligand of this family, NDF, could induce such effects in the ma mmary gland in vivo, We therefore targeted expression of NDF to the ma mmary gland of transgenic mice using the mouse mammary tumor virus (MM TV) promoter in a fusion a clear, but subtle effect on adult virgin gl and of female transgenic animals, Terminal end bud structures (TEBs), which normally disappear from the mammary gland at the age of similar to 8 weeks in wild type mice, persist in glands of virgin MMTV-NDF tra nsgenic females, suggesting that NDF inhibits signals that normally le ad to the terminal differentiation of these structures, Further, femal e mice, bred continuously to maximize expression of the transgene in t he mammary gland,develop mammary adenocarcinomas at a median age of 12 months, Since these tumors arise in a solitary fashion, we infer that NDF is necessary, but not sufficient for their formation, In order to explore the signal transduction pathways potentially activated by NDF , we examined expression of the receptors erbB2, erbB3 and erbB4 in ma mmary epithelial cells established from induced tumor, All three recep tors were though only the erbB3 receptor was phosphorylated, suggestin g that overexpression of NDF might operate through this receptor, Addi tionally, about 50% of MMTV-NDF transgenic mice developed Harderian (l achrymal) gland hyperplasia, a benign tumor that does not progress to frank malignacy.