Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers

We have shown recently (B. A. Yoshida et al., Cancer Res., 59: 5483-5487) t hat mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo. Evaluation of the expression of compon ents of the MKK4 signaling cascade showed a loss or downregulation of expre ssion of MKK4 or c-Jun, a downstream mediator of MKK4, in six of eight huma n prostate cancer cell lines. Given these findings, we next assessed whethe r MKK4 dysregulation occurs during the development of clinical prostate can cer. Immunohistochemical studies showed high levels of MKK4 expression in t he epithelial but not the stromal compartment of normal prostatic tissues. In neoplastic tissues, a statistically significant, direct, inverse relatio nship between Gleason pattern and MKK4 was established, These results demon strate that MKK4 protein is consistently down-regulated during prostate can cer progression and support a role for dysregulation of its signaling casca de in clinical disease. To test the possibility that down-regulation of MKK 4 protein is the result of allelic loss, metastatic prostate cancer lesions were examined for loss of heterozygosity (LOH) within the MKK4 locus (D17S 969). These studies showed a 31% (5 of 16) LOH of MMK4 that is not associat ed with coding region mutations, which suggests that the nucleotide sequenc e of the gene in the remaining allele is infrequently mutated.