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BRCA Mutations and Breast Cancer Prevention
Open AccessArticle

CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

1
Department of Oncology and Hematology, UniversitätsSpital Zürich, Rämistrasse 100, 0832 Zürich 1, The Netherlands
2
Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
3
Department of Breast Medical Oncology, UT-MD Anderson Cancer Center, Houston, TX 77030, USA
4
Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA
5
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
6
Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
*
Authors to whom correspondence should be addressed.
Cancers 2018, 10(12), 525; https://doi.org/10.3390/cancers10120525
Received: 11 November 2018 / Revised: 11 December 2018 / Accepted: 13 December 2018 / Published: 19 December 2018
Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials. View Full-Text
Keywords: triple negative breast cancer (TNBC); cancer stem cells (CSC); CREB-binding protein (CBP); forkhead box protein M1 (FOXM1); ICG-001 triple negative breast cancer (TNBC); cancer stem cells (CSC); CREB-binding protein (CBP); forkhead box protein M1 (FOXM1); ICG-001
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MDPI and ACS Style

Ring, A.; Nguyen, C.; Smbatyan, G.; Tripathy, D.; Yu, M.; Press, M.; Kahn, M.; Lang, J.E. CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer. Cancers 2018, 10, 525.

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