Activation of the Wnt signalling pathway is a recognised early event in many intestinal cancers. Mouse models of intestinal neoplasia have proven to be invaluable in increasing our knowledge and understanding relating to the contribution of individual genes in this process. We have previously used Cre-Lox technology to conditionally delete the
Apc gene in the mouse intestine and characterised the phenotypic and transcriptional changes that occur following the acute activation of Wnt signalling in this tissue [
1]. Our microarray analysis demonstrated transcriptional activation of the Hormonally upregulated Neu-associated kinase (
HUNK/Mak-v/Bstk1) gene immediately following
Apc loss, indicating that
Hunk is potentially a Wnt signalling target gene which could play a role during the initial stages of intestinal neoplasia. Hunk is a SNF1(sucrose non fermenting 1)-related serine/ threonine kinase that was originally cloned by Korobko
et al. [
2,
3] and Gardner
et al. [
4] but its function still remains largely unknown. A variety of binding partners for Hunk have been identified including Nedd4 E3 ubiquitin ligase [
5], Synaptopodin [
6], Rabaptin-5 [
7] and cofilin-1 [
8], although the molecular mechanisms of Hunk action remain unclear.
Hunk has been shown to be expressed in a variety of tissues but is most notably associated with pregnancy-induced alterations in the mammary gland and high levels of expression within the brain [
4,
9]. Two independent studies have shown that Hunk is able to negatively regulate proliferation in normal epithelial cells. Gain-of-function and loss-of-function studies within mouse distal convoluted tubule (mDCT) cells, demonstrated that Hunk negatively regulates ANG II-induced c-fos gene expression and mDCT proliferation [
10]. Furthermore, MMTV-driven Hunk over-expression within mammary epithelium, inhibits proliferation of alveolar epithelial cells during mid-pregnancy [
9]. However, within the cancer setting, both pro- and antitumourigenic properties for Hunk have been described. Overexpression of
Hunk has been shown in a number of different cancers, and it is thought to be associated with the more aggressive subset of carcinomas [
11,
12], probably due to its ability to support cell viability and survival [
3,
13,
14]. Using transgenic mouse models, Yeh
et al. [
13] have shown that
Hunk plays a role in tumour initiation and is required to facilitate HER2/neu-induced mammary tumourigensis. Contrary to this, Wertheim
et al. [
12] demonstrated that
Hunk was dispensable for tumour initiation in a MMTV-cMyc driven model of mammary tumourigenesis, but was essential for tumour metastasis, and therefore impacted on overall survival in this mouse tumour model. Both of these studies suggest Hunk functions in a pro-tumourigenic manner. Conversely, in a xenograft model of mammary tumourigenesis using a basal breast cancer cell line in which
Hunk was over expressed, Quintela-Fandino
et al. [
8] demonstrate that Hunk overexpression suppresses metastasis, suggesting a tumour suppressor role for Hunk. However, the differences in the experimental setup of these studies make it difficult to draw any firm conclusions as to the role of Hunk in tumourigenesis. Although over-expression of
Hunk has been shown to be associated with advanced and aggressive forms of carcinoma [
12], no one to date has studied the importance of
Hunk in intestinal tumourigenesis. Indeed, analysis of the Oncomine database confirmed the association of
Hunk expression and intestinal cancer. For breast cancer, the cancer conventionally associated with Hunk, 1 out of 27 analyses (3.7%) within the Oncomine database demonstrate greater than 1.5 fold over-expression of
Hunk (p < 0.01). However, using the same cut-off criteria, 5 out of 24 analyses (28.8%) associated with colorectal cancer. This clearly indicates that overexpression of
Hunk is potentially important in intestinal cancer and warrants further investigation.