A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1

Olga C. Rodriguez, Edwin W. Lai, Sarada Vissapragada, Caroline Cromelin, Maral Avetian, Patricia Salinas, Hida Ramos, Bhaskar Kallakury, Mathew Casimiro, Michael P. Lisanti, Herbert B. Tanowitz, Karel Pacak, Robert I. Glazer, Maria Avantaggiati, Chris Albanese

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18 Scopus citations

Abstract

Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2-induced prostate epithelial proliferation is not well understood. In the Pten-deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin-driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that monoallelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB-2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade.

Original languageEnglish (US)
Pages (from-to)2051-2060
Number of pages10
JournalAmerican Journal of Pathology
Volume174
Issue number6
DOIs
Publication statusPublished - Jun 2009

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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