ALTERATIONS IN PANCREATIC, BILIARY, AND BREAST CARCINOMAS SUPPORT MKK4 AS A GENETICALLY TARGETED TUMOR-SUPPRESSOR GENE

Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involvin g MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phosphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human p ancreatic, lung, breast, testicle, and colorectal cancer cell lines su ggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypica l for many human tumor suppressor genes, and constitutional DNA was no t previously available to determine whether the reported sequence vari ants had preceded tumor development. Here, we report that homozygous d eletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addit ion, in a panel of 45 pancreatic carcinomas prescreened for loss of he terozygosity, one somatic missense mutation of MKK4 is observed and co nfirmed in the primary tumor (2%), Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion, The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MK K4 may participate in a tumor suppressive signaling pathway distinct f rom DPC4, p16, p53, and BRCA2.