Siegel Peter M, Shu Weiping, Cardiff Robert D, Muller William J, Massagué Joan
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8430-5. doi: 10.1073/pnas.0932636100. Epub 2003 Jun 13.
The influence of transforming growth factor beta (TGF-beta) signaling on Neu-induced mammary tumorigenesis and metastasis was examined with transgenic mouse models. We generated mice expressing an activated TGF-beta type I receptor or dominant negative TGF-beta type II receptor under control of the mouse mammary tumor virus promoter. When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 or Shc signaling pathways the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis. Conversely, expression of the dominant negative type II receptor decreased the latency of Neu-induced mammary tumor formation while significantly reducing the incidence of extravascular lung metastases. These observations argue that TGF-beta can promote the formation of lung metastases while impairing Neu-induced tumor growth and suggest that extravasation of breast cancer cells from pulmonary vessels is a point of action of TGF-beta in the metastatic process.
利用转基因小鼠模型研究了转化生长因子β（TGF-β）信号传导对Neu诱导的乳腺肿瘤发生和转移的影响。我们构建了在小鼠乳腺肿瘤病毒启动子控制下表达活化的TGF-β I型受体或显性负性TGF-β II型受体的小鼠。当与表达选择性偶联至Grb2或Shc信号通路的活化形式的Neu受体酪氨酸激酶的小鼠杂交时，活化的I型受体增加了乳腺肿瘤形成的潜伏期，但也提高了血管外肺转移的频率。相反，显性负性II型受体的表达缩短了Neu诱导的乳腺肿瘤形成的潜伏期，同时显著降低了血管外肺转移的发生率。这些观察结果表明，TGF-β可促进肺转移的形成，同时损害Neu诱导的肿瘤生长，并提示乳腺癌细胞从肺血管外渗是TGF-β在转移过程中的作用点。
