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

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


PROVIDER: S-EPMC4198744 | BioStudies | 2014-01-01T00:00:00Z

REPOSITORIES: biostudies

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