The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis

Abstract

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.breast cancer ͉ knockout mice ͉ mouse models ͉ protein kinase

HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1

“…Our results stand in contrast to those of the Chodosh group, who reported that levels of HUNK in normal murine mammary gland varied with the estrus cycle (6). This group has also described upregulation of HUNK in several (unspecified) human breast cancer cell lines and in a mammary-specific MYC-transgenic mouse model (8). In that study, it was suggested that HUNK kinase activity is important for the metastasis of HER-2 and luminal breast cancer cells.…”

“…The Chodosh group has reported that deletion of HUNK on an MMTV-MYC background diminishes metastases, as measured by direct observation of necropsied lungs (8). However, the mechanism underlying this reduction was not explored.…”

“…In normal murine mammary cells, HUNK levels vary with the hormonal cycle (6). With respect to transformed cells, Wertheim et al recently reported that HUNK is highly expressed in cells derived from HER-2 and luminal breast cancers and suggested that HUNK kinase function is essential for the ability of these cells to establish metastases in a MMTV-MYC mouse model (8).…”

Oncogenes and Tumor Suppressor Genes

“…The enhanced metastatic phenotypes that have been observed in various AKT models have recently been linked to AKTmediated suppression of the miR 200 micro-RNA, which suppresses the epithelial -mesenchymal transition in epithelial cells ). Knocking out another kinase in this pathway-the Snf1-related serine kinase Hunk-abrogates the metastatic phenotype in an ErbB2 mouse tumor model (Wertheim et al 2009). Oncogenic activation of the different serine kinases may thus have distinct effects on the induction and metastatic phases of mammary tumor development.…”

De-amping the HER2 environment

“…4 Hunk deficiency delayed tumor development in transgenic mice with Her2-driven breast cancer and decreased the average number of tumors per mouse by about 50% compared with Hunk expression, suggesting that the kinase is involved in HER2-driven tumorigenesis.…”