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Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression.

Publication ,  Journal Article
Kohn, EA; Yang, Y-A; Du, Z; Nagano, Y; Van Schyndle, CMH; Herrmann, MA; Heldman, M; Chen, J-Q; Stuelten, CH; Flanders, KC; Wakefield, LM
Published in: Mol Cancer Res
October 2012

TGF-β 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-β 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-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β 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-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis.

Duke Scholars

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

October 2012

Volume

10

Issue

10

Start / End Page

1389 / 1399

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad3 Protein
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Binding
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Mice
  • Mammary Glands, Human
  • Mammary Glands, Animal
 

Citation

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MLA
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Kohn, E. A., Yang, Y.-A., Du, Z., Nagano, Y., Van Schyndle, C. M. H., Herrmann, M. A., … Wakefield, L. M. (2012). Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res, 10(10), 1389–1399. https://doi.org/10.1158/1541-7786.MCR-12-0136-T
Kohn, Ethan A., Yu-an Yang, Zhijun Du, Yoshiko Nagano, Catherine M. H. Van Schyndle, Michelle A. Herrmann, Madeleine Heldman, et al. “Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression.Mol Cancer Res 10, no. 10 (October 2012): 1389–99. https://doi.org/10.1158/1541-7786.MCR-12-0136-T.
Kohn EA, Yang Y-A, Du Z, Nagano Y, Van Schyndle CMH, Herrmann MA, et al. Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res. 2012 Oct;10(10):1389–99.
Kohn, Ethan A., et al. “Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression.Mol Cancer Res, vol. 10, no. 10, Oct. 2012, pp. 1389–99. Pubmed, doi:10.1158/1541-7786.MCR-12-0136-T.
Kohn EA, Yang Y-A, Du Z, Nagano Y, Van Schyndle CMH, Herrmann MA, Heldman M, Chen J-Q, Stuelten CH, Flanders KC, Wakefield LM. Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res. 2012 Oct;10(10):1389–1399.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

October 2012

Volume

10

Issue

10

Start / End Page

1389 / 1399

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Smad3 Protein
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Binding
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Mice
  • Mammary Glands, Human
  • Mammary Glands, Animal