PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-kappa B-Cytokine Network

Ying, H. Q., Elpek, K. G., Vinjamoori, A., Zimmerman, S. M., Chu, G. C., Yan, H. Y., Fletcher-Sananikone, E., Zhang, H. L., Liu, Y. C., Wang, W., Ren, X. J., Zheng, H. W., Kimmelman, A. C., Paik, J. H., Lim, C., Perry, S. R., Jiang, S., Malinn, B., Protopopov, A., Colla, S., Xiao, Y. H., Hezel, A. F., Bardeesy, N., Turley, S. J., Wang, Y. A. A., Chin, L., Thayer, S. P., DePinho, R. A. (July 2011) PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-kappa B-Cytokine Network. Cancer Discovery, 1 (2). pp. 158-169. ISSN 2159-8274

URL: http://www.ncbi.nlm.nih.gov/pubmed/21984975
DOI: 10.1158/2159-8290.cd-11-0031

Abstract

Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-kappa B activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-kappa B network, which may serve to shape the PDAC tumor microenvironment. SIGNIFICANCE: Detailed molecular genetics studies established that PTEN operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development. The strong activation of the NF-kappa B-cytokine program in Pten-deficient tumors provides additional avenues for targeted therapies in tumors with altered PI3K regulation. Cancer Discovery; 1(2); 158-69. (C)2011 AACR.

Item Type: Paper
Uncontrolled Keywords: K-RAS MOUSE MODEL PHOSPHATIDYLINOSITOL 3-KINASE MALIGNANT-TRANSFORMATION CANCER DEVELOPMENT CELLS EXPRESSION PROGRESSION MUTATIONS SUBUNIT Oncology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: July 2011
Date Deposited: 22 Aug 2014 20:12
Last Modified: 22 Aug 2014 20:12
PMCID: PMC3186945
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30698

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