D'souza B, Taylor-Papadimitriou J
Epithelial Cell Biology Laboratory, Imperial Cancer Research Fund, London, England.
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7202-6. doi: 10.1073/pnas.91.15.7202.
Overexpression of the ERBB2 receptor in transfectants of a human mammary epithelial cell line (MTSV1-7) is associated with a reduced ability to undergo morphogenesis in vitro and with a decreased level of expression of the E-cadherin and alpha 2 integrin genes. The inhibition of expression of the adhesion molecules has been shown to be at the level of transcription by using nuclear run-on assays and by following transcription of a reporter gene fused to 5' sequences of the E-cadherin gene. To relate the effects on gene transcription to a functional ERBB2 protein, signaling from the receptor was inhibited by the antibody 4D5, which blocks phosphorylation of ERBB2 on tyrosine residues and association of the protein with the GRB2/Sem5 protein. After treatment with the antibody 4D5, the ERBB2 transfectants regain the ability to form three-dimensional structures in collagen gels and the rates of transcription of the genes encoding the E-cadherin and the alpha 2 integrin subunit are restored to the levels seen in MTSV1-7neo cells. These results demonstrate that the inhibition of morphogenesis and transcription of specific adhesion molecules in human mammary epithelial cells can be affected by signals generated by the ERBB2 receptor and suggest a role for ERBB2 overexpression in tumor progression and metastasis.
在人乳腺上皮细胞系（MTSV1-7）的转染子中，ERBB2受体的过表达与体外形态发生能力降低以及E-钙黏蛋白和α2整合素基因表达水平降低相关。通过核转录分析以及追踪与E-钙黏蛋白基因5'序列融合的报告基因的转录，已表明黏附分子表达的抑制发生在转录水平。为了将对基因转录的影响与功能性ERBB2蛋白联系起来，用抗体4D5抑制受体信号传导，该抗体可阻断ERBB2酪氨酸残基的磷酸化以及该蛋白与GRB2/Sem5蛋白的结合。用抗体4D5处理后，ERBB2转染子恢复了在胶原凝胶中形成三维结构的能力，并且编码E-钙黏蛋白和α2整合素亚基的基因的转录速率恢复到MTSV1-7neo细胞中的水平。这些结果表明，人乳腺上皮细胞中形态发生和特定黏附分子转录的抑制可能受ERBB2受体产生的信号影响，并提示ERBB2过表达在肿瘤进展和转移中起作用。
