Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC
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Kaihua Zhang1, Lamont Jones1, Sora Lim1, Christopher A. Maher1,2, Douglas Adkins1,2 , James Lewis2,3, Randall J. Kimple4, Elana J. Fertig5, Christine H. Chung5, Andreas Herrlich6, Matthew J. Ellis1,2, Brian A. Van Tine1,2 and Loren S. Michel1,2
1 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
2 The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
3 Department of Pathology, Washington University School of Medicine, St. Louis, Missouri
4 Department of Human Oncology, University of Wisconsin, Madison, Wisconsin
5 Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
6 Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Loren Michel, email:
Keywords: Trop2, ErbB3, Head and Neck Squamous Cell Carcinoma (HNSCC), Neuregulin-1, Therapy
Received: April 22, 2014 Accepted: September 02, 2014 Published: September 02, 2014
In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics.
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