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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Abstract
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-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-β 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-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.