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

Cancers

Debu Tripathy¹  Cu Nguyen²  Goar Smbatyan²  Michael Kahn²  Alexander Ring³  Min Yu⁴  Michael Press⁵  JulieE. Lang⁵ 

[1] Department of Breast Medical Oncology, UT-MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;Department of Oncology and Hematology, UniversitätsSpital Zürich, Rämistrasse 100, 0832 Zürich 1, The Netherlands;Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA;University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA;

关键词: triple negative breast cancer (TNBC);    cancer stem cells (CSC);    CREB-binding protein (CBP);    forkhead box protein M1 (FOXM1);    ICG-001;   

DOI  :  10.3390/cancers10120525

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown