| First Author | Kohn EA | Year | 2012 |
| Journal | Mol Cancer Res | Volume | 10 |
| Issue | 10 | Pages | 1389-99 |
| PubMed ID | 22878587 | Mgi Jnum | J:318836 |
| Mgi Id | MGI:6861990 | Doi | 10.1158/1541-7786.MCR-12-0136-T |
| Citation | Kohn EA, et al. (2012) Biological responses to TGF-beta in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res 10(10):1389-99 |
| abstractText | TGF-beta plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-beta signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-beta. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-beta responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3(+/-) IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-beta in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis. |
