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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 p27(kip1). 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.

SUBMITTER: Yeh ES

PROVIDER: S-EPMC3049391 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Yeh Elizabeth S ES Yang Thomas W TW Jung Jason J JJ Gardner Heather P HP Cardiff Robert D RD Chodosh Lewis A LA

The Journal of clinical investigation 20110301 3

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 b ...[more]

PMID: 21393859

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Project description:Our previous studies demonstrated that selective overexpression of the Ron receptor tyrosine kinase in the murine mammary epithelium leads to mammary tumor formation. Biochemical analysis of mammary tumor lysates showed that Ron overexpression was associated with increases in ?-catenin expression and tyrosine phosphorylation. ?-Catenin has also been shown to be regulated through tyrosine phosphorylation by the receptor tyrosine kinases Met, Fer and Fyn. However, the molecular and physiological roles of ?-catenin and ?-catenin tyrosine phosphorylation downstream of Ron are not known. To investigate this association, we show that Ron and ?-catenin are coordinately elevated in human breast cancers. Our data also demonstrate that activation of Ron, through ligand binding by hepatocyte growth factor-like protein (HGFL), induces the tyrosine phosphorylation of ?-catenin, primarily on tyrosine residues Tyr 654 and Tyr 670. In addition, HGFL-mediated Ron activation induces both ?-catenin nuclear localization and transcriptional activity, with Tyr 654 and Tyr 670 residues of ?-catenin being critical for these processes. We also demonstrate that a knockdown of Ron in breast cancer cell lines leads to a loss of HGFL-induced ?-catenin-dependent transcriptional activation and cell growth, which can be rescued by activation of canonical Wnt/?-catenin signaling. Moreover, we show that HGFL-dependent Ron activation mediates upregulation of the ?-catenin target genes cyclin D1 and c-myc, and that expression of these target genes in breast cancer cells is decreased following inhibition of Ron and/or ?-catenin. Finally, we show that genetic ablation of ?-catenin in Ron-expressing breast cancer cells decreases cellular proliferation in vitro, as well as mammary tumor growth and metastasis, following orthotopic transplantation into the mammary fat pad. Together, our data suggest that ?-catenin is a crucial downstream regulator of Ron receptor activation and is an important mediator of mammary tumorigenesis.

Dataset Information

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

Publications

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

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