Data from Transforming Growth Factor-β (TGF-β)–Inducible Gene <i>TMEPAI</i> Converts TGF-β from a Tumor Suppressor to a Tumor Promoter in Breast Cancer

TMEPAI is a transforming growth factor-β (TGF-β)–induced transmembrane protein that is overexpressed in several cancers. How TMEPAI expression relates to malignancy is unknown. Here, we report high expression of TMEPAI in estrogen receptor/progesterone receptor–negative and human epidermal growth factor receptor-2–negative breast cancer cell lines and primary breast cancers that was further increased by TGF-β treatment. Basal and TGF-β–induced expression of TMEPAI were inhibited by the TGF-β receptor antagonist SB431542 and overexpression of Smad7 or a dominant-negative mutant of Alk-5. TMEPAI knockdown attenuated TGF-β–induced growth and motility in breast cancer cells, suggesting a role for TMEPAI in growth promotion and invasiveness. Further, TMEPAI knockdown decreased breast tumor mass in a mouse xenograft model in a manner associated with increased expression of phosphatase and tensin homologue (PTEN) and diminished phosphorylation of Akt. Consistent with the effects through the phosphatidylinositol 3-kinase pathway, tumors with TMEPAI knockdown exhibited elevated levels of the cell cycle inhibitor p27kip1 and attenuated levels of DNA replication and expression of hypoxia-inducible fator 1α and vascular endothelial growth factor. Together, these results suggest that TMEPAI functions in breast cancer as a molecular switch that converts TGF-β from a tumor suppressor to a tumor promoter. Cancer Res; 70(15); 6377–83. ©2010 AACR.