TY - JOUR
TI - Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells
AU - Wan, X.
AU - Liu, J.
AU - Lu, J.-F.
AU - Tzelepi, V.
AU - Yang, J.
AU - Starbuck, M.W.
AU - Diao, L.
AU - Wang, J.
AU - Efstathiou, E.
AU - Vazquez, E.S.
AU - Troncoso, P.
AU - Maity, S.N.
AU - Navone, N.M.
JO - Clinical Cancer Research
PY - 2012
VL - 18
TODO - 3
SP - 726-736
PB - 
SN - 1078-0432
TODO - 10.1158/1078-0432.CCR-11-2521
TODO - androgen receptor;  beta catenin;  hyaluronic acid;  Wnt protein, animal cell;  animal experiment;  animal model;  animal tissue;  article;  bone metastasis;  cancer cell;  clinical article;  codon;  controlled study;  enzyme activation;  enzyme activity;  enzyme synthesis;  gene sequence;  gene silencing;  Has2 gene;  human;  human cell;  human tissue;  immunocytochemistry;  male;  mouse;  nonhuman;  oncogene;  priority journal;  prostate cancer;  protein function;  protein localization;  protein protein interaction;  signal transduction, Animals;  beta Catenin;  Blotting, Western;  Bone Neoplasms;  Gene Expression Profiling;  Glucuronosyltransferase;  Humans;  Immunohistochemistry;  Male;  Mice;  Mice, SCID;  Mutation;  Prostatic Neoplasms;  Real-Time Polymerase Chain Reaction;  Receptors, Androgen;  Reverse Transcriptase Polymerase Chain Reaction;  Signal Transduction;  Transplantation, Heterologous
TODO - Purpose: To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction. Experimental Design: We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin-mediated transcription), and sequenced the β-catenin gene inMDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. Results: β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P=0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. Conclusion: We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients. ©2011 AACR.
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