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.

Hunk negatively regulates c-myc to promote Akt-mediated cell survival and mammary tumorigenesis induced by loss of Pten

“…Although Hunk has previously been implicated in mammary tumorigenesis as well as metastasis, a physiological role for this kinase has not been defined (2,3,5). We now demonstrate that Hunk maintains the balance between cell survival and cell death during mammary gland development by suppressing the upregulation of myc that normally occurs during postlactational involution.…”

“…Recently, we demonstrated that Hunk is required for the survival and growth of HER2/neu-driven tumor cells as a consequence of Hunk-dependent regulation of p27 kip1 protein levels and subcellular localization (3). Hunk also reportedly promotes the survival of PC12 neuronal cells, although the underlying mechanism has not been elucidated (4).…”

“…Hunk also reportedly promotes the survival of PC12 neuronal cells, although the underlying mechanism has not been elucidated (4). Additional evidence indicates that Hunk mediates epidermal growth factor receptor (EGFR) and HER2/ neu signaling and that Hunk expression is up-regulated by these pathways and by their effector pathways Akt and MAPK (3,5). Together, these observations suggest that Hunk promotes cell survival and may serve as an effector of growth factor signaling.…”

PET Imaging of Glutaminolysis in Tumors by 18F-(2S,4R)4-Fluoroglutamine

“…We decided to use m/tomND transgenic mice with spontaneous mammary gland tumors as a model for testing, because they are closer to the native than the xenografted tumor model. We used HER2/neu expression controlled by doxycycline administered through the drinking water to develop a mouse tumor model (m/tomND transgenic mice) in which myc expression could be manipulated (37,38). These mice spontaneously grow mammary gland tumors in a few weeks, and myc expression in the tumors was upregulated by 2-fold under doxycycline-triggered myc upregualtion (Alveraz and Chodosh, unpublished data, 2011).…”

Apoptosis of Breast Cancer Cells: Modulation of Genes for Glycoconjugate Biosynthesis and Targeted Drug Delivery

“…16.1 ) of breast cancer cells are not completely understood (Lee et al 2010 ;Deng et al 2010 ;de Graauw et al 2010 ;Araki et al 2010 ;Singh et al 2010 ) . Analysis of Hunk (−/−) mice revealed that this Kinase is required (Yeh et al 2011 ) for metastasis of c-myc-induced mammary tumors, but not c-myc-induced primary transformed cells.…”