YAP and β-Catenin Cooperate to Drive Oncogenesis in Basal Breast Cancer
- 15 April 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (8), 2116-2127
- https://doi.org/10.1158/0008-5472.CAN-20-2801
Abstract
Targeting cancer stem cells (CSC) can serve as an effective approach toward limiting resistance to therapies. While basal-like (triple-negative) breast cancers encompass cells with CSC features, rational therapies remain poorly established. We show here that the receptor tyrosine kinase Met promotes YAP activity in basal-like breast cancer and find enhanced YAP activity within the CSC population. Interfering with YAP activity delayed basal-like cancer formation, prevented luminal to basal transdifferentiation, and reduced CSC. YAP knockout mammary glands revealed a decrease in beta-catenin target genes, suggesting that YAP is required for nuclear beta-catenin activity. Mechanistically, nuclear YAP interacted with beta-catenin and TEAD4 at gene regulatory elements. Proteomic patient data revealed an upregulation of the YAP signature in basal-like breast cancers. Our findings demonstrate that in basal-like breast cancers, b-catenin activity is dependent on YAP signaling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/beta-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal-like breast cancers. Significance: These findings show that YAP cooperates with b-catenin in basal-like breast cancer to regulate CSCs and that targeting this interaction may be a novel CSC therapy for patients with basal-like breast cancer.Other Versions
Funding Information
- theNetworking Fund of the Helmholtz Association (VH-KO-612)
- ICRF (2028184)
- ISF (2027619)
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