JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

The c-Jun NH ₂-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) con...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (30), p.12046-12051
Main Authors:	Hübner, Anette, Mulholland, David J, Standen, Claire L, Karasarides, Maria, Cavanagh-Kyros, Julie, Barrett, Tamera, Chi, Hongbo, Greiner, Dale L, Tournier, Cathy, Sawyers, Charles L, Flavell, Richard A, Wu, Hong, Davis, Roger J
Format:	Article
Language:	eng
Subjects:	Adenocarcinoma Adenocarcinoma - physiopathology Animals Biological Sciences Cancer carcinogenesis Cell Transformation, Neoplastic - metabolism Cells Epithelium Histological Techniques JNK Mitogen-Activated Protein Kinases - metabolism Kinases Lesions Male MAP Kinase Signaling System - physiology Metastasis Mice Mice, Transgenic Microscopy, Fluorescence mitogen-activated protein kinase Prostate Prostate cancer Prostate gland prostatic neoplasms Prostatic Neoplasms - physiopathology PTEN Phosphohydrolase - metabolism Rodents Signal transduction Stem cells Tumors
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Summary:	The c-Jun NH ₂-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN signaling pathways can cooperate to regulate the progression of prostate neoplasia to invasive adenocarcinoma.
ISSN:	0027-8424 1091-6490