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Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor
G H Su1, W Hilgers, M C Shekher
1Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Abstract:
Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving 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 pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions 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 addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed 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 MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.
Insights
Mitogen-activated protein kinase kinase 4 (MKK4) acts as a tumor suppressor. Homozygous deletions and mutations in MKK4 were found in pancreatic, biliary, and breast cancers, supporting its role in tumor suppression.
Area of Science:
- Molecular Biology
- Oncology
- Signal Transduction
Background:
- Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is involved in stress and cytokine-induced signaling pathways.
- MKK4 activates JNK1 and p38 MAPK through phosphorylation.
- Previous studies suggested MKK4's role in tumor suppression, with gene alterations found in various cancer cell lines.
Purpose of the Study:
- To investigate the role of MKK4 as a tumor suppressor gene.
- To determine the frequency of MKK4 gene deletions and mutations in primary human cancers.
- To confirm MKK4 as a mutationally targeted tumor suppressor gene.
Main Methods:
- Analysis of homozygous deletions in pancreatic, biliary, and breast adenocarcinomas.
- Detection of somatic mutations in MKK4 in pancreatic carcinomas.
- Mapping of homozygous deletions to confirm MKK4 as the target.
Main Results:
- Homozygous deletions of MKK4 were detected in 2% of pancreatic adenocarcinomas, 6% of biliary adenocarcinomas, and 14% of breast carcinomas (including sequence alterations).
- A somatic missense mutation in MKK4 was identified in 2% of analyzed pancreatic carcinomas.
- MKK4 was confirmed as a target of deletion and mutation in these cancers.
Conclusions:
- MKK4 functions as a tumor suppressor gene.
- Alterations in MKK4 are implicated in the development of pancreatic, biliary, and breast cancers.
- MKK4 may operate in a distinct tumor suppressive pathway separate from other known tumor suppressor genes.