Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells.
OBJECTIVE
To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction.


METHODS
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 in MDA 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.


CONCLUSIONS
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.
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Xinhai
X
Wan
Jie
J
Liu
Jing-Fang
JF
Lu
Vassiliki
V
Tzelepi
Jun
J
Yang
Michael W
MW
Starbuck
Lixia
L
Diao
Jing
J
Wang
Eleni
E
Efstathiou
Elba S
ES
Vazquez
Patricia
P
Troncoso
Sankar N
SN
Maity
Nora M
NM
Navone
D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C495270:CTNNB1 protein, human; D011944:Receptors, Androgen; D051176:beta Catenin; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases