Activation of β-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells
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Abstract
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 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. 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. Clin Cancer Res; 18(3); 726–36. ©2011 AACR.
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β-catenin, a critical mediator of the WNT signaling pathway, plays an important role in tumorigenesis.
“β-catenin, a critical mediator of the WNT signaling pathway, plays an important role in tumorigenesis.441–444”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [444]
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- [36]Provost E McCabe A Stern J Lizardi I D’Aquila TG Rimm DL Functional correlates of mutation of the Asp32 and Gly34 residues of beta-catenin Oncogene 2005 Apr 14 24 16 2667 76 15829978
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Wan, X., Liu, J., Lu, J.-F., Tzelepi, V., Yang, J., Starbuck, M. W., Diao, L., Wang, J., Efstathiou, E., Vazquez, E. S., Troncoso, P., Maity, S. N., & Navone, N. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Navone, Nora M.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-01-31
- Volume
- 18
- Issue
- 3
- Pages
- 726-736
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3271798
- OpenAlex
- W2116718088
- Cited by
- 79
- References
- 41
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 10 · 2020: 4 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 7 · 2014: 6 · 2013: 8 · 2012: 5
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- National Cancer Institute (CA 016672, P50CA140388, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- β-catenin signaling, Wnt/β-catenin signaling, castration-resistant prostate cancer, androgen receptor-negative prostate cancer, HAS2, bone metastasis, extracellular matrix, downstream target genes, β-catenin nuclear localization
- MeSH terms
- Hyaluronan Synthases, Animals, Bone Neoplasms, Humans, Immunohistochemistry, Male, Mutation, Prostatic Neoplasms, Receptors, Androgen, Transplantation, Heterologous, Glucuronosyltransferase, Blotting, Western, Signal Transduction, Mice, SCID, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, beta Catenin, Mice, Real-Time Polymerase Chain Reaction
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