Transforming Growth Factor β Engages TACE and ErbB3 To Activate Phosphatidylinositol-3 Kinase/Akt in ErbB2-Overexpressing Breast Cancer and Desensitizes Cells to Trastuzumab

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 PI3K/Akt. RNA interference of TACE or ErbB3 prevented TGF-β-induced activation of Akt and cell invasiveness. Treatment with TGF-β or expression of Alk5^T204D 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 Alk5^T204D 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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

This work was supported by NCI 1K99 CA125892 (S.E.W.), American Cancer Society-Institutional Research Grant IRG-58-009-49 (S.E.W.), grant BFU2006-01813/BMC from the Ministry of Science and Education of Spain (A.P.), NCI R01 CA62212 (C.L.A.), R01 CA80195 (C.L.A.), NIH R01 DE017982 (C.H.C.), the Damon Runyon Clinical Investigator Award CI-28-05 (C.H.C.), Breast Cancer Specialized Program of Research Excellence) P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center support grant P30 CA68485.

We thank Harold Moses, Brent Rexer, Brian Bierie, Nikki Cheng (Vanderbilt), and Ben Turk (Yale University) for valuable comments and the Vanderbilt Microarray Shared Resource for expert assistance.