title: A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1.
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 mono-allelic 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.
authors.affiliation: Departments of Oncology and Pathology, Lombardi Comprehensive Cancer Center. Georgetown University Medical Center. Washington, DC 20057, USA.
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Lai
authors.forename: Sarada
authors.initials: S
authors.lastname: Vissapragada
authors.forename: Caroline
authors.initials: C
authors.lastname: Cromelin
authors.forename: Maral
authors.initials: M
authors.lastname: Avetian
authors.forename: Patricia
authors.initials: P
authors.lastname: Salinas
authors.forename: Hida
authors.initials: H
authors.lastname: Ramos
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Mathew
authors.initials: M
authors.lastname: Casimiro
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Robert I
authors.initials: RI
authors.lastname: Glazer
authors.forename: Maria
authors.initials: M
authors.lastname: Avantaggiati
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; C487757:Pten protein, mouse