The Balance of Cell Surface and Soluble Type III TGF-β Receptor Regulates BMP Signaling in Normal and Cancerous Mammary Epithelial Cells

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