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Functional Analysis of SMAD Activation in TGF-B-Mediated Negative Growth Control in Breast Epithelial Cells

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Annual rept. 16 Mar 1998-15 Mar 2001

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The ability of transforming growth factor-beta TGF-beta to potently suppress the proliferation of normal breast epithelial cells may be central to its putative role in tumor suppression of early stage breast cancers. Thus, the elucidation of the mechanisms by which TGF-beta is able to exert these effects is relevant to the further understanding of breast cancer initiation and possibly prevention. The purpose of these studies is to further define the role of the Smads as TGF-beta-activated transcriptional regulators with particular attention to target genes involved in cellular growth inhibition, and thus, genes potentially involved in the tumor suppression of early breast cancers. The proto- ohcogene c-Myc is repressed by TGE-beta and this repression is paramount for the manifestation of TGE-beta mediated growth arrest of epithelial cells. We have shown that Smad3 is required for both TGF-beta induced c-Myc repression and subsequently growth arrest in epithelial cells. The transcriptional repression of c-Myc is dependent on Smad3 binding to a novel Smad binding element within the TGE-beta Inhibitory Element TIE of the c-Myc promoter, termed a Repressive Smad Binding Element ESBE . In conclusion, we have established Smad3 as an essential component of TGF-beta induced growth inhibition and contributed to the understanding of how this growth arrest program is initiated.

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  • Medicine and Medical Research

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