Abstract
BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene. Chemotherapy remains the standard of care for TNBC treatment, but considerable patients are very resistant to chemotherapy. Mutations or aberrant upregulation of EZH2 occur frequently, and EZH2 inhibitor (EZH2i) showed some preclinic antitumor effects in TNBC.MethodsRNA-seq data of 3 TNBC cell lines either treated with 2 μM GSK343, or stably transduced with shEHZ2, compared to untreated controls (GSE112378) were analyzed by Limma R package. The Kaplan–Meier plotter (KM plotter) database was used to assess the relevance of FOSB mRNA expression to relapse-free survival (RFS) in TNBC. Cell number counting and colony formation assays were used to detect the biological effect of FOSB on the growth of TNBC cells in vitro. The effect of FOSB on TNBC tumor growth in vivo was investigated in a mice tumor xenograft model. Luciferase reporter and chromatin immunoprecipitation (Chip) assays were used to determine the regulatory roles of C/EBPβ on FOSB expression.ResultsWe found that FOSB, a member of the activator protein-1 complex, was a direct downstream target of EZH2. FOSB was significantly decreased in TNBC samples and associated with better relapse-free survival (RFS). EZH2-mediated histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation, at the FOSB promoter inhibited it expression. Depletion of FOSB in TNBC cells promoted cell proliferation in vitro and tumor growth in vitro by inactivating the p53 pathway and conferred resistant to EZH2 inhibitor (EZH2i). Mechanistically, EZH2i promotes the shift from H3K27me3 to H3K27ac at the FOSB promoter, and recruits the transcription factor C/EBPβ to activate FOSB gene transcription.ConclusionTogether, our results suggest that EZH2-mediated epigenetic inactivation of FOSB promotes TNBC expression and demonstrate that reactivation of FOSB expression by C/EBPβ underlies the anti-TNBC action of EZH2is.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene
As FOSB has been reported to be activated in several kinds of tumors, we hypothesized that FOSB may be a critical downstream target gene of EZH2 and mediate the function of EZH2 inhibitor (EZH2i) in TNBC
Consistent with the RNA sequencing analysis (RNA-seq) data, we found that GSK343 treatment significantly increased FOSB mRNA and protein expression in MDA-MB-231 and MDA-MB-436, two TNBC cell lines (Fig. 1b, c)
Summary
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene. Breast cancer is a heterogeneous disease that differs in morphology, molecular biology, clinical manifestations, and responsiveness to treatment [1]. Zhang et al Cancer Cell Int (2020) 20:175 into four subtypes: the mammary glandular type, the human epidermal growth factor-2 overexpression type, the normal cell-like type, and the basal-like type [2]. Triple-negative breast cancer (TNBC) is an aggressive basal-like subtype that constitutes 12–18% of breast cancer patients and frequently develops resistance to chemotherapy [3]. Different strategies were used to treatment breast cancer in preclinical models [5,6,7]. Epigenetic mechanisms have been discovered to play an important role in the development of TNBC and targeting epigenetic enzymes might represent a novel treatment for TNBC patient [8, 9]
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