Krane I M, Leder P
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Oncogene. 1996 Apr 18;12(8):1781-8.
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 potential ligand of this family, NDF, could induce such effects in the mammary gland in vivo. We therefore targeted expression of NDF to the mammary gland of transgenic mice using the mouse mammary tumor virus (MMTV) promoter in a fusion construct. There was a clear, but subtle effect on development of the adult virgin gland of female transgenic animals. Terminal end bud structures (TEBs), which normally disappear from the mammary gland at the age of approximately 8 weeks in wild type mice, persist in glands of virgin MMTV-NDF transgenic females, suggesting that NDF inhibits signals that normally lead to the terminal differentiation of these structures. Further, female mice, bred continuously to maximize expression of the transgene in the 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 mammary epithelial cells established from an NDF-induced tumor. All three receptors were expressed, though only the erbB3 receptor was phosphorylated, suggesting that overexpression of NDF might operate through this receptor. Additionally, about 50% of MMTV-NDF transgenic mice developed Harderian (lachrymal) gland hyperplasia, a benign tumor that does not progress to frank malignancy.
神经分化因子（NDF）是erbB受体配体神经调节蛋白家族的成员，对培养的人乳腺上皮细胞具有诱导分化和促有丝分裂的作用。由于包括Neu/erbB2在内的表皮生长因子受体家族成员与乳腺癌有关，我们想知道该家族的潜在配体NDF是否能在体内乳腺中诱导此类效应。因此，我们使用融合构建体中的小鼠乳腺肿瘤病毒（MMTV）启动子，将NDF的表达靶向到转基因小鼠的乳腺。对雌性转基因动物成年处女乳腺的发育有明显但细微的影响。终末芽结构（TEB）在野生型小鼠中通常在约8周龄时从乳腺消失，而在MMTV-NDF转基因处女雌性小鼠的腺体中持续存在，这表明NDF抑制了通常导致这些结构终末分化的信号。此外，持续繁殖以最大化转基因在乳腺中表达的雌性小鼠，在12个月的中位年龄时发生乳腺腺癌。由于这些肿瘤以孤立的方式出现，我们推断NDF对其形成是必要的，但不是充分的。为了探索可能由NDF激活的信号转导途径我们检测了从NDF诱导的肿瘤建立的乳腺上皮细胞中erbB2、erbB3和erbB4受体的表达。所有三种受体均有表达，尽管只有erbB3受体被磷酸化，这表明NDF的过表达可能通过该受体起作用。此外，约50%的MMTV-NDF转基因小鼠发生了哈德氏（泪腺）腺增生，这是一种不会发展为明显恶性肿瘤的良性肿瘤。
