Chen C R, Kang Y, Massagué J
Cell Biology Program, Memorial Sloan-Kettering Cancer Center and Howard Hughes Medical Institute, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):992-9. doi: 10.1073/pnas.98.3.992.
Loss of growth inhibitory responses to the cytokine transforming growth factor beta (TGF-beta) in cancer cells may result from mutational inactivation of TGF-beta receptors or their signal transducers, the Smad transcription factors. In breast cancer, however, loss of TGF-beta growth inhibition often occurs without a loss of these signaling components. A genome-wide analysis of rapid TGF-beta gene responses in MCF-10A human mammary epithelial cells and MDA-MB-231 breast cancer cells shows that c-myc repression, a response that is key to the TGF-beta program of cell cycle arrest, is selectively lost in the cancer cell line. Transformation of MCF-10A cells with c-Ha-ras and c-erbB2 oncogenes also led to a selective loss of c-myc repression and cell cycle arrest response. TGF-beta stimulation of epithelial cells rapidly induces the formation of a Smad complex that specifically recognizes a TGF-beta inhibitory element in the c-myc promoter. Formation of this complex is deficient in the oncogenically transformed breast cells. These results suggest that a Smad complex that specifically mediates c-myc repression is a target of oncogenic signals in breast cancer.
癌细胞对细胞因子转化生长因子β（TGF-β）的生长抑制反应丧失，可能是由于TGF-β受体或其信号转导分子（Smad转录因子）发生突变失活所致。然而，在乳腺癌中，TGF-β生长抑制作用的丧失往往并不伴随着这些信号成分的缺失。对MCF-10A人乳腺上皮细胞和MDA-MB-231乳腺癌细胞中TGF-β基因快速反应进行的全基因组分析表明，c-myc基因的抑制作用——这是TGF-β诱导细胞周期停滞程序的关键反应——在癌细胞系中选择性丧失。用c-Ha-ras和c-erbB2癌基因转化MCF-10A细胞，也导致c-myc基因抑制作用和细胞周期停滞反应的选择性丧失。TGF-β刺激上皮细胞会迅速诱导形成一种Smad复合物，该复合物能特异性识别c-myc启动子中的TGF-β抑制元件。在致癌转化的乳腺细胞中，这种复合物的形成存在缺陷。这些结果表明，特异性介导c-myc基因抑制作用的Smad复合物是乳腺癌致癌信号的作用靶点。
