Inhibiting Wnt/beta‐catenin in CTNNB1 ‐mutated endometrial cancer
| العنوان: | Inhibiting Wnt/beta‐catenin in CTNNB1 ‐mutated endometrial cancer |
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| المؤلفون: | Andrew P. Bradford, Elizabeth R. Woodruff, Benjamin G. Bitler, Rebecca J. Wolsky, Lubna Qamar, Marisa R. Moroney, Bradley R. Corr |
| المصدر: | Molecular Carcinogenesis. 60:511-523 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Indazoles, Cell Survival, Pyridines, T cell, Cell, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, In vivo, Cell Line, Tumor, medicine, Humans, Molecular Targeted Therapy, Viability assay, Wnt Signaling Pathway, Molecular Biology, beta Catenin, Imidazoles, Wnt signaling pathway, Disease Management, Deoxyuridine, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, Wnt Proteins, 030104 developmental biology, medicine.anatomical_structure, chemistry, Tumor progression, Cell culture, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Disease Susceptibility, Heterocyclic Compounds, 3-Ring |
| الوصف: | The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5'-bromo-2'-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690. Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC. |
| تدمد: | 1098-2744 0899-1987 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::94f3e519848e57026bec21f10348f445 https://doi.org/10.1002/mc.23308 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....94f3e519848e57026bec21f10348f445 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10982744 08991987 |
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