DPC4/SMAD4 mutations are associated with aggressive pancreatic cancer.In this issue of Cell, Whittle et al. demonstrate that Runx3 expression combined with Dpc4/Smad4 status can predict the metastatic propensity of pancreatic tumors, providing valuable guidance for personalized therapy for patients with pancreatic cancer.
A panel of human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice and pancreatic cancer cell lines were studied. p15 gene alterations, mainly homozygous deletions that involved exons 1 and/or 2, were found in the 62.5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations were found in one of eight xenografts and in two of seven cell lines.
Activation of the proto-oncogene K-Ras and inactivation of the tumour suppressor gene loci INK4a, p53 and SMAD4 are characteristic for pancreatic cancer.
As a central player in TGF-β signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer.
DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-beta (TGFbeta)-suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGFbeta growth-inhibitory and transcriptional responses were found to be DPC4-independent.
Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer.
Finally, a Smad4 mutation identified in a human pancreatic carcinoma that inactivates Smad4 signaling abolished Smad4 DNA binding activity, hence preventing transactivation of TGFbeta-responsive genes.
Genetic mutations, such as activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A, inactivation of the tumor-suppressor gene TP53 and deleted in pancreatic cancer 4 (DPC4) gene defects are seen in those with pancreatic cancer.
However, <i>smad4/DPC4</i> is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies.
In the present study, we analyzed 15 human pancreatic cancer cell lines for genetic alterations of the K-ras, p53, p16, and SMAD4 genes, which are very frequent targets for mutation in pancreatic cancer; these cell lines are useful resources in cancer research.
In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations.
In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets.
Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis.