Hunk is required for HER2/neu-induced mammary tumorigenesis

Elizabeth S. Yeh, Thomas W. Yang, Jason J. Jung, Heather P. Gardner, Robert Cardiff, Lewis A. Chodosh

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)866-879
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number3
DOIs
StatePublished - Mar 1 2011

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Carcinogenesis
Breast
Breast Neoplasms
Phosphotransferases
Neoplasms
AMP-Activated Protein Kinases
myc Genes
Aptitude
Ovarian Neoplasms
Colonic Neoplasms
Transgenic Mice
Cell Survival
Down-Regulation
Maintenance
Apoptosis
Neoplasm Metastasis
Phenotype
Cell Line
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yeh, E. S., Yang, T. W., Jung, J. J., Gardner, H. P., Cardiff, R., & Chodosh, L. A. (2011). Hunk is required for HER2/neu-induced mammary tumorigenesis. Journal of Clinical Investigation, 121(3), 866-879. https://doi.org/10.1172/JCI42928

Hunk is required for HER2/neu-induced mammary tumorigenesis. / Yeh, Elizabeth S.; Yang, Thomas W.; Jung, Jason J.; Gardner, Heather P.; Cardiff, Robert; Chodosh, Lewis A.

In: Journal of Clinical Investigation, Vol. 121, No. 3, 01.03.2011, p. 866-879.

Research output: Contribution to journalArticle

Yeh, ES, Yang, TW, Jung, JJ, Gardner, HP, Cardiff, R & Chodosh, LA 2011, 'Hunk is required for HER2/neu-induced mammary tumorigenesis', Journal of Clinical Investigation, vol. 121, no. 3, pp. 866-879. https://doi.org/10.1172/JCI42928
Yeh, Elizabeth S. ; Yang, Thomas W. ; Jung, Jason J. ; Gardner, Heather P. ; Cardiff, Robert ; Chodosh, Lewis A. / Hunk is required for HER2/neu-induced mammary tumorigenesis. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 3. pp. 866-879.
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