Muller W J, Arteaga C L, Muthuswamy S K, Siegel P M, Webster M A, Cardiff R D, Meise K S, Li F, Halter S A, Coffey R J
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Mol Cell Biol. 1996 Oct;16(10):5726-36. doi: 10.1128/MCB.16.10.5726.
Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal 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 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-alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-alpha and neu in the mammary epithelium. Female mice coexpressing TGF-alpha 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-alpha cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.
在乳腺上皮中表达神经原癌基因或转化生长因子（TGF-α）的转基因小鼠会发生自发性局灶性乳腺肿瘤，且潜伏期较长。由于表皮生长因子受体（EGFR）和Neu能够形成对诸如TGF-α等EGFR配体有反应的异二聚体，我们研究了TGF-α和Neu在乳腺上皮中的共表达是否会协同作用以加速乳腺肿瘤的发生。为了验证这一假设，我们将分别携带小鼠乳腺肿瘤病毒/TGF-α或小鼠乳腺肿瘤病毒/neu转基因的不同转基因品系进行杂交，以产生在乳腺上皮中共表达TGF-α和neu的双转基因小鼠。共表达TGF-α和neu的雌性小鼠发生了多灶性乳腺肿瘤，其出现的潜伏期明显短于单独的亲本品系。这些乳腺肿瘤的发生与Neu的酪氨酸磷酸化以及c-Src向Neu复合物的募集相关。然而，用EGFR和Neu特异性抗血清进行免疫沉淀和免疫印迹分析未能检测到这两种受体的物理复合物。综上所述，这些观察结果表明Neu和TGF-α通过涉及Neu和EGFR反式激活的机制在乳腺肿瘤发生过程中协同作用。
