Transforming growth factor β engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab

Shizhen Emily Wang, Bin Xiang, Marta Guix, Maria Graciela Olivares, Joel Parker, Christine H. Chung, Atanasio Pandiella, Carlos L. Arteaga

Research output: Contribution to journalArticle

123 Scopus citations

Abstract

In HER2-overexpressing mammary epithelial cells, transforming growth factor β (TGF-β) activated phosphatidylinositol-3 kinase (PI3K)/Akt and enhanced survival and migration. Treatment with TGF-β or expression of an activated TGF-β type I receptor (Alk5 with the mutation T204D [Alk5 T204D]) induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface, resulting in increased secretion of TGF-α, amphiregulin, and heregulin. In turn, these ligands enhanced the association of p85 with ErbB3 and activated PDK/Akt. RNA interference of TACE or ErbB3 prevented TGF-β-induced activation of Akt and cell invasive-ness. Treatment with TGF-β or expression of Alk5T204D in HER2-overexpressing cells reduced their sensitivity to the HER2 antibody trastuzumab. Inhibition of Alk5, PI3K, TACE, or ErbB3 restored sensitivity to trastuzumab. A gene signature induced by Alk5T204D expression correlated with poor clinical outcomes in patients with invasive breast cancer. These results suggest that by acting on ErbB ligand shedding, an excess of TGF-β may result in (i) conditioning of the tumor microenvironment with growth factors that can engage adjacent stromal and endothelial cells; (ii) potentiation of signaling downstream ErbB receptors, thus contributing to tumor progression and resistance to anti-HER2 therapies; and (iii) poor clinical outcomes in women with breast cancer.

Original languageEnglish (US)
Pages (from-to)5605-5620
Number of pages16
JournalMolecular and cellular biology
Volume28
Issue number18
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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