Journal
CANCERS
Volume 10, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/cancers10120525
Keywords
triple negative breast cancer (TNBC); cancer stem cells (CSC); CREB-binding protein (CBP); forkhead box protein M1 (FOXM1); ICG-001
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Funding
- CIRM clinical fellowship [TG2-01161]
- Susan G. Komen Foundation [53-5178-6040]
- National Cancer Institute [P30CA014089]
- NIH [1R01CA166161-01A1, 1R21NS074392-01, 1R21AI105057-01, NIH 1R01 HL112638-01]
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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/beta-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of GBP/beta-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/beta-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/beta-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.
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