Abstract
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.
Highlights
Breast cancer (BC) is a heterogeneous disease [1], yet clinical management is based on only three biomarkers: estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor (HER2) [2]
Increased expression of CREB-binding protein (CBP) was observed in BC compared to normal breast and in Triple negative breast cancers (TNBCs) compared to other BC
Protein levels of CBP were high in TNBC cell lines (MDA-MB-231 and MDA-MB-468) compared to the non-tumorigenic breast epithelial cell line MCF10a (Figure 1C)
Summary
Breast cancer (BC) is a heterogeneous disease [1], yet clinical management is based on only three biomarkers: estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor (HER2) [2]. CREB-binding protein (CBP) and/or E1A-associated protein p300 (p300) are important co-activators in β-catenin-driven transcription [11] and play critical roles in various cellular functions such as proliferation, cell cycle regulation and apoptosis [12] Despite their high degree of homology, both proteins have distinct functions [13], in particular in stem cell biology, either maintaining an undifferentiated state or inducing differentiation, respectively [14]. FOXM1 is one of the most commonly up-regulated transcripts in various cancers, including breast cancer [17] It is critically important for cell cycle progression [18] and plays a key role in therapy resistance [19]. We identified the CBP/β-catenin/FOXM1 transcriptional complex as an important driver in TNBC biology and a potential novel therapeutic target
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