title: In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis.
abstract: Understanding the molecular etiology of prostate cancer (CaP) progression is paramount for broadening current diagnostic and therapeutic modalities. Current interest in the role of wnt pathway signaling in prostate tumorigenesis was generated with the finding of beta-catenin mutation and corresponding nuclear localization in primary lesions. The recent finding of beta-catenin-induced enhancement of androgen receptor (AR) function potentially ties beta-catenin to key regulatory steps of prostate cell growth, differentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear beta-catenin in 20% of lethal CaP cases, suggesting a more common role for beta-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, beta-catenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate beta-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of beta-catenin signaling in prostate cells. Extending our previous findings, we demonstrate that transient beta-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to cross-regulation by phosphoinositide-3-kinase (PI3-K)/Akt signaling, a stimulatory pathway often upregulated in CaP upon PTEN inactivation. Consistent with a previous report, we observed that transient beta-catenin over-expression enhances AR-mediated transcription off two natural target gene promoters. However, we were unable to recapitulate beta-catenin-induced stimulation of ectopically expressed AR in AR-negative cells, suggesting that other AR-associated factors are required for this activity. Although LNCaP cells are capable of this mode of AR co-stimulation, stable expression of mutant beta-catenin did not alter their proliferative response to androgen. In total, our characterization of beta-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that beta-catenin potentially contributes to multiple stimulatory inputs required for disease progression.
authors.affiliation: Brady Urological Institute Research Laboratories, The Johns Hopkins Medical Institutions, Baltimore, Maryland, MD 21287, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Chesire
authors.forename: Charles M
authors.initials: CM
authors.lastname: Ewing
authors.forename: Wesley R
authors.initials: WR
authors.lastname: Gage
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: D003598:Cytoskeletal Proteins; D008156:Luciferases; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C544894:TCF7L2 protein, human; C553059:Tcf7l2 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C446603:TPTE protein, human