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The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells.

Publication ,  Journal Article
Gatza, CE; Elderbroom, JL; Oh, SY; Starr, MD; Nixon, AB; Blobe, GC
Published in: Neoplasia
June 2014

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-β receptor (TβRIII) mediates BMP signaling. While TβRIII expression is lost during breast cancer progression, the role of TβRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TβRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TβRIII expression in human breast cancer cell lines or treatment with sTβRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TβRIII, TβRIII over-expression, or treatment with sTβRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TβRIII shedding through treatment with TAPI-2 or expression of a non-shedding TβRIII mutant rescued TβRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TβRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TβRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTβRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTβRIII plays an important role in mediating these effects.

Duke Scholars

Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

June 2014

Volume

16

Issue

6

Start / End Page

489 / 500

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • Humans
  • Female
  • Epithelial Cells
  • Disease Models, Animal
 

Citation

APA
Chicago
ICMJE
MLA
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Gatza, C. E., Elderbroom, J. L., Oh, S. Y., Starr, M. D., Nixon, A. B., & Blobe, G. C. (2014). The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells. Neoplasia, 16(6), 489–500. https://doi.org/10.1016/j.neo.2014.05.008
Gatza, Catherine E., Jennifer L. Elderbroom, Sun Young Oh, Mark D. Starr, Andrew B. Nixon, and Gerard C. Blobe. “The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells.Neoplasia 16, no. 6 (June 2014): 489–500. https://doi.org/10.1016/j.neo.2014.05.008.
Gatza CE, Elderbroom JL, Oh SY, Starr MD, Nixon AB, Blobe GC. The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells. Neoplasia. 2014 Jun;16(6):489–500.
Gatza, Catherine E., et al. “The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells.Neoplasia, vol. 16, no. 6, June 2014, pp. 489–500. Pubmed, doi:10.1016/j.neo.2014.05.008.
Gatza CE, Elderbroom JL, Oh SY, Starr MD, Nixon AB, Blobe GC. The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells. Neoplasia. 2014 Jun;16(6):489–500.
Journal cover image

Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

June 2014

Volume

16

Issue

6

Start / End Page

489 / 500

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • Humans
  • Female
  • Epithelial Cells
  • Disease Models, Animal