Hunk is required for HER2/neu-induced mammary tumorigenesis
Elizabeth S. Yeh, … , Robert D. Cardiff, Lewis A. Chodosh
Elizabeth S. Yeh, … , Robert D. Cardiff, Lewis A. Chodosh
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):866-879. https://doi.org/10.1172/JCI42928.
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Research Article Oncology

Hunk is required for HER2/neu-induced mammary tumorigenesis

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.

Authors

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

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Figure 3

Hunk is required for HER2/neu-induced mammary tumorigenesis.

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Hunk is required for HER2/neu-induced mammary tumorigenesis. (A) Tumor-f...
(A) Tumor-free survival curves comparing MMTV-neu;Hunk–wild-type with MMTV-neu;Hunk–deficient mice. P = 0.001; HR = 2.4. (B) Tumor-free survival curves comparing MTB/TAN;Hunk–wild-type with MTB/TAN;Hunk-deficient mice treated with 0.1 mg/ml doxycycline. P = 0.0001; HR 4.4. (C) Average number of tumors per animal in MMTV-neu;Hunk–wild-type (n = 22) and MMTV-neu;Hunk–deficient mice (n = 16). All 10 mammary glands were examined at necropsy to determine total tumor number per animal. *P < 0.01. Data represent mean ± SEM. (D) Average number of tumors per animal in MTB/TAN;Hunk–wild-type mice (n = 12) and MTB/TAN;Hunk-deficient mice (n = 14) treated with 0.1 mg/ml doxycycline. *P < 0.05. Data represent mean ± SEM. (E) Whole-mount analysis of carmine-stained non–tumor-bearing glands from MMTV-neu;Hunk–wild-type and MMTV-neu;Hunk–deficient mice. White arrows indicate focal hyperplasias. (F) Hematoxylin and eosin staining of a representative hyperplasia (top) and tumor (bottom) from a MMTV-neu;Hunk–wild-type mouse. Original magnification, ×6.3 (E); ×200 (F). (G) Quantification of the total number of lesions in non–tumor-bearing glands isolated from MMTV-neu;Hunk–wild-type mice and MMTV-neu;Hunk–deficient mice. *P < 0.05. Data represent mean ± SEM.