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J Clin Invest. doi:10.1172/JCI42928.
Copyright © 2011, The American Society for Clinical Investigation
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Research Article

Hunk is required for HER2/neu-induced mammary tumorigenesis

Elizabeth S. Yeh1, Thomas W. Yang1, Jason J. Jung1, Heather P. Gardner1, Robert D. Cardiff2 and Lewis A. Chodosh1

1Department of Cancer Biology, Department of Cell and Developmental Biology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
2Department of Pathology and Laboratory Medicine School of Medicine, University of California Davis Center for Comparative Medicine, UCD, Davis, California, USA.

Address correspondence to: Lewis A. Chodosh, 612 BRB II/III, 421 Curie Boulevard, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA. Phone: 215.898.1321; Fax: 215.573.6725; E-mail: chodosh@mail.med.upenn.edu.

Published February 14, 2011
Received for publication March 10, 2010, and accepted in revised form December 29, 2010.

Understanding the molecular pathways that contribute to the aggressive behavior of human cancers is a critical research priority. The SNF1/AMPK-related protein kinase Hunk is overexpressed in aggressive subsets of human breast, ovarian, and colon cancers. Analysis of Hunk–/– mice revealed that this kinase is required for metastasis of c-myc–induced mammary tumors but not c-myc–induced primary tumor formation. Similar to c-myc, amplification of the proto-oncogene HER2/neu occurs in 10%–30% of breast cancers and is associated with aggressive tumor behavior. By crossing Hunk–/– mice with transgenic mouse models for HER2/neu-induced mammary tumorigenesis, we report that Hunk is required for primary tumor formation induced by HER2/neu. Knockdown and reconstitution experiments in mouse and human breast cancer cell lines demonstrated that Hunk is required for maintenance of the tumorigenic phenotype in HER2/neu-transformed cells. This requirement is kinase dependent and resulted from the ability of Hunk to suppress apoptosis in association with downregulation of the tumor suppressor p27kip1. Additionally, we find that Hunk is rapidly upregulated following HER2/neu activation in vivo and in vitro. These findings provide what we believe is the first evidence for a role for Hunk in primary tumorigenesis and cell survival and identify this kinase as an essential effector of the HER2/neu oncogenic pathway.