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PMID: 18625725 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 28 ·No. 18 ·2008-09-00 ·Pages 5605-20

Wang SE, Xiang B, Guix M, Olivares MG, Parker J, Chung CH, Pandiella A, Arteaga CL

Abstract

In HER2-overexpressing mammary epithelial cells, transforming growth factor beta (TGF-beta) activated phosphatidylinositol-3 kinase (PI3K)/Akt and enhanced survival and migration. Treatment with TGF-beta or expression of an activated TGF-beta 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-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-beta-induced activation of Akt and cell invasiveness. Treatment with TGF-beta 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-beta 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.

MeSH Terms
ADAM Proteins/genetics,metabolism ADAM17 Protein Antibodies, Monoclonal/therapeutic use Antibodies, Monoclonal, Humanized Antineoplastic Agents/therapeutic use Breast Neoplasms/drug therapy,genetics,metabolism,pathology Cells, Cultured Enzyme Activation Female Gene Expression Profiling Humans Oligonucleotide Array Sequence Analysis Phosphatidylinositol 3-Kinases/genetics,metabolism Proto-Oncogene Proteins c-akt/genetics,metabolism RNA Interference Receptor, ErbB-2/genetics,metabolism Signal Transduction/physiology Transforming Growth Factor alpha/metabolism Transforming Growth Factor beta/metabolism Trastuzumab Treatment Outcome
Chemicals
Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Transforming Growth Factor alpha Transforming Growth Factor beta Phosphatidylinositol 3-Kinases Receptor, ErbB-2 Proto-Oncogene Proteins c-akt ADAM Proteins ADAM17 Protein ADAM17 protein, human Trastuzumab
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Wang Shizhen Emily
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. emily.wang@vanderbilt.edu
Xiang Bin
Guix Marta
Olivares Maria Graciela
Parker Joel
Chung Christine H
Pandiella Atanasio
Arteaga Carlos L
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00787-08
Email
emily.wang@vanderbilt.edu
Published
2008-09-00
Epub
2008-00-14
Pages
5605-20
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2546920
Subset
IM
Grants
NCI NIH HHS · R01 CA080195 · United States
NCI NIH HHS · R01 CA062212 · United States
NCI NIH HHS · P50 CA98131 · United States
NCI NIH HHS · K99 CA125892 · United States
NCI NIH HHS · P30 CA068485 · United States
NCI NIH HHS · R00 CA125892 · United States
NCI NIH HHS · P30 CA68485 · United States
NCI NIH HHS · 1K99 CA125892 · United States
NIDCR NIH HHS · R01 DE017982 · United States
NCI NIH HHS · R01 CA80195 · United States
NCI NIH HHS · R01 CA62212 · United States
NCI NIH HHS · P50 CA098131 · United States
External Links
PubMed source DOI: 10.1128/MCB.00787-08 PMC Full Text View journal details
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