Loss of growth inhibitory responses to the cytokine transforming growth factor β (tgf-β) in cancer cells may result from mutational inactivation of Tgf-β receptors or their signal transducers, the Smad transcription factors. In breast cancer, however, loss of Tgf-β growth inhibition often occurs without a loss of these signaling components. A genome-wide analysis of rapid Tgf-β gene responses in Mcf-1oa human mammary epithelial cells and Mda-mb-231 breast cancer cells shows that c-myc repression, a response that is key to the Tgf-β program of cell cycle arrest, is selectively lost in the cancer cell line. Transformation of Mcf-1oa 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-β stimulation of epithelial cells rapidly induces the formation of a Smad complex that specifically recognizes a Tgf-β 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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jan 30 2001|
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