Defective repression of c-myc in breast cancer cells:: A loss at the core of the transforming growth factor β growth arrest program
Defective repression of c-myc in breast cancer cells:: A loss at the core of the transforming growth factor β growth arrest program
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DOI：
10.1073/pnas.98.3.992
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发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Massagué, J
中科院分区：
文献类型：
--
作者：
Chen, CR;Kang, YB;Massagué, J
肿瘤细胞对细胞因子转化生长因子-β的生长抑制反应的丧失可能是由于转化生长因子-β受体或其信号转导Smad转录因子突变失活所致。然而，在乳腺癌中，转化生长因子-β生长抑制的丧失通常不会丢失这些信号成分。对MCF-10A人乳腺上皮细胞和MDA-MB-231乳腺癌细胞的快速转化生长因子-β基因反应的全基因组分析表明，c-myc抑制是细胞周期停滞的转化生长因子-β程序的关键反应，在癌细胞系中选择性地丢失。C-Ha-ras和c-erbB2癌基因转化的MCF-10A细胞也导致c-myc抑制和细胞周期停滞反应的选择性丧失。转化生长因子-β刺激上皮细胞迅速诱导形成Smad复合体，该复合体特异性地识别c-myc启动子中的转化生长因子-β抑制元件。这种复合体的形成在致癌转化的乳腺细胞中是缺乏的。这些结果表明，特异性地介导c-myc抑制的Smad复合体是乳腺癌致癌信号的靶点。
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.