Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program.
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.
Chen
C R
CR
Cell Biology Program, Memorial Sloan-Kettering Cancer Center and Howard Hughes Medical Institute, New York, NY 10021, USA.
Kang
Y
Y
Massagué
J
J
D001483:Base Sequence; D001940:Breast; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta