Abstract 3971: The type III tgf-β receptor mediates bmp signaling in normal and cancerous mammary epithelial cells

Abstract

Abstract BMP signaling has been shown to enhance breast cancer invasion and bone metastasis, while inhibition of BMP signaling abrogates bone metastasis in an in vivo model. The type III TGF-β receptor (TβRIII) is known to mediate BMP signaling and can inhibit migration, invasion, and metastasis in breast cancer, however the role of TβRIII in regulating BMP signaling in breast cancer has not been examined. The MDA-MB-231, MCF7, and mouse 4T1 breast cancer cell lines, which express low levels of TβRIII, are responsive to BMP2 and 4 treatment as demonstrated by increased Smad1/5/8 phosphorylation, cell migration, and invasion. Restoring TβRIII expression in these cell lines or treatment of MDA-MB-231-Neo cells with recombinant soluble TβRIII (sTβRIII) or with conditioned media from MDA-MB-231-RIII cells inhibited BMP2 and BMP4 induced Smad1/5/8 phosphorylation (pSmad1/5/8) and BMP mediated cell migration. MDA-MB-231-RIII cells also exhibited enhanced growth arrest in response to BMP2 compared to MDA-MB-231-Neo cells, mediated through the up-regulation of p21. In reciprocal studies, shRNA-mediated knockdown of TβRIII expression in the normal mammary epithelial cell lines HMEC and MCF10A, abrogated BMP mediated induction of pSmad1/5/8, demonstrating that TβRIII mediates BMP signaling in normal mammary epithelial cells. Additionally, treatment with both recombinant sTβRIII and conditioned media from MDA-MB-231-RIII cells inhibits BMP mediated induction of pSmad1/5/8, suggesting that sTβRIII is able to inhibit BMP signaling in normal mammary epithelial cells by sequestration of ligand. BMP2 treatment induces cell migration in HMEC cells, which was attenuated by knockdown of TβRIII or treatment with sTβRIII. These data demonstrate that TβRIII mediates BMP signaling in normal mammary epithelial cells and breast cancer cell lines, regulating cell migration, invasion, and proliferation. The effects of sTβRIII suggest that the ratio of membrane bound versus soluble TβRIII plays an important role in mediating BMP signaling and cellular effects in normal and cancer mammary epithelial cells. Further work is underway to elucidate the mechanism by which TβRIII regulates BMP signaling in breast cancer in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3971.