Transforming growth factor-β (TGF-β)-inducible gene TMEPAI converts TGF-β from a tumor suppressor to a tumor promoter in breast cancer

Prajjal K. Singha, I. Tien Yeh, Manjeri A. Venkatachalam, Pothana Saikumar

Resultado de la investigación: Articlerevisión exhaustiva

61 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)6377-6383
Número de páginas7
PublicaciónCancer Research
Volumen70
N.º15
DOI
EstadoPublished - ago. 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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