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Molecular and Cellular Biology, September 2008, p. 5605-5620, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00787-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Shizhen Emily Wang,1,4* Bin Xiang,2 Marta Guix,2 Maria Graciela Olivares,3 Joel Parker,5 Christine H. Chung,1,2 Atanasio Pandiella,6 and Carlos L. Arteaga1,2,4*

Departments of Cancer Biology,1 Medicine,2 Pathology,3 Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee,4 Expression Analysis, Durham, North Carolina,5 Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain6

Received 15 May 2008/ Returned for modification 25 June 2008/ Accepted 2 July 2008

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 [Alk5T204D]) induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface, resulting in increased secretion of TGF-{alpha}, 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 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.

* Corresponding author. Mailing address for Carlos L. Arteaga: Division of Oncology, Vanderbilt University School of Medicine, 2200 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: (615) 936-3524. Fax: (615) 936-1790. E-mail: carlos.arteaga{at}vanderbilt.edu. Mailing address for Shizhen Emily Wang: Department of Cancer Biology, Vanderbilt University School of Medicine, 2200 Pierce Avenue, 771 PRB, Nashville, TN 37232-6840. Phone: (615) 936-3761. Fax: (615) 936-1790. E-mail: emily.wang{at}vanderbilt.edu

{triangledown} Published ahead of print on 14 July 2008.

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

Molecular and Cellular Biology, September 2008, p. 5605-5620, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00787-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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