Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia

Identification of the signalling cascades that are differentially activated during prostatic tumourigenesis is a crucial step in the search for future molecular targets in this disease. The stress-activated protein kinase (SAPK) signalling cascade culminates in the phosphorylation of the JNK and p38 mitogen-activated protein kinases (MAPKs). Recently, the upstream activators of these proteins, the MAPK kinases (MKKs), have been implicated as inhibitors of tumour progression in a variety of clinical and experimental tumour models. This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse prostate (TRAMP) model of prostate tumourigenesis. Benign prostate, prostatic intraepithelial neoplasia (PIN) lesions and tumour tissues were collected from 37 TRAMP mice. Additionally, six tissue microarrays were constructed with tumours from a matched group of 102 men who underwent radical prostatectomy. Tissues from 20 patients with extensive high-grade prostatic intraepithelial neoplasia (HGPIN) were also analysed. For all samples, immunohistochemical staining for MKK4, MKK6 and MKK7 was scored in normal and neoplastic glands. Staining intensities of MKK4, MKK6 and MKK7 were significantly increased in HGPIN and prostate cancer compared to surrounding normal glands in both the TRAMP and human samples (p < 0.0001 for all markers). Increased levels of MKK4 or MKK7 correlated with higher pathological stage at prostatectomy (p = 0.01 and p = 0.04). Using multivariate analysis, there was no association between protein levels and time to biochemical recurrence in the human samples. The up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression in both TRAMP and human tissues highlights an important role for the SAPK signalling cascade in prostatic neoplasia. The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis.