NFE2L3 Regulates the Expression of BHLHE40 in Triple-Negative Breast Cancer

Shail Rakesh Modi,Terrick Andey,George Acquaah-Mensah

Cancer Research（2024）

1Massachusetts Col. of Pharmacy & Health Sci.

Cited 0|Views10
Abstract
Abstract Introduction: Breast Cancer (BrCA) is one of the most common cancers, causing mortality in women worldwide. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is the most aggressive due to the absence of three major receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). Treatment options for TNBC are limited because of the lack of these molecular targets. We hypothesized that the identification and characterization of novel transcriptional regulatory relationships in TNBC will provide etiologic insights, enhance therapeutic outcomes, and improve patient survival. Overexpression of NFE2L3 in BrCA has inhibited cell proliferation and metastasis while overexpression of BHLHE40 has produced an inverse effect. This study aims to characterize the relationship between NFE2L3 and BHLHE40 in TNBC cells. Methods: Patient data from the two groups of our focus from the Cancer Genome Atlas BrCA RNAseq gene expression dataset were examined: triple-positive breast cancer (TPBC) and TNBC. Differentially expressed genes (DEGs) between these groups were identified using DESeq2. Pathways over-represented among the DEGs were determined using enrichR. For their impact on biological interactions, those DEGs were mapped to curate protein-protein interactions - the STRING database. Additionally, DEGs were superposed on two network inference algorithm-generated transcriptional regulatory networks (TRNs). Virtual Inference of protein activity by Enriched Regulon analysis was applied to the generated TRN to identify master regulators driving gene expression differences between TPBC and TNBC. Of the master regulators observed, the activity of NFE2L3 was explored in TNBC cells. The TRNs indicate that NFE2L3 regulates the expression of BHLHE40. This regulatory relationship was explored in TNBC cells by RNA interference, qRT-PCR, immunoblotting, and co-immunoprecipitation assays to investigate NFE2L3 and BHLHE40 gene and protein expression and interaction. Results: Among 12,000 DEGs (5% FDR), over-represented pathways included “mitotic signaling” and “G1/S transition”. Master regulators with higher expression in TNBC included NFE2L3, HMGA1, TP53, FOXC1, and SOX9; those with lower expression included FOXA1, BHLHE40, AR, XBP1, and ESR1. On silencing the cells of NFE2L3 and performing qRTPCR analysis, the expression of BHLHE40 was decreased in the TNBC cells. The protein-protein interaction between NFE2L3 and BHLHE40 was also validated. Conclusion: DEGs up-regulated in TNBC participate in cell cycle signaling. And there is a novel transcriptional regulatory relationship between NFE2L3 and BHLHE40 in TNBC cells. Citation Format: Shail Rakesh Modi, Terrick Andey, George Acquaah-Mensah. NFE2L3 regulates the expression of BHLHE40 in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4883.
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【要点】：研究揭示了NFE2L3与BHLHE40在TNBC细胞中的新型转录调控关系，NFE2L3调节BHLHE40的表达，可能为TNBC的治疗提供新策略。


【方法】：利用Cancer Genome Atlas BrCA RNAseq基因表达数据集，通过差异表达基因分析、通路富集分析、蛋白质-蛋白质相互作用映射和网络推断算法，识别TNBC中的关键调控因子，并通过实验方法验证NFE2L3和BHLHE40之间的调控关系。


【实验】：通过RNA干扰、qRT-PCR、免疫印迹和共免疫沉淀实验在TNBC细胞中探索NFE2L3和BHLHE40的基因和蛋白表达及其相互作用，发现沉默NFE2L3后BHLHE40的表达量下降，且NFE2L3和BHLHE40之间存在蛋白质-蛋白质相互作用。使用的数据集为Cancer Genome Atlas BrCA RNAseq基因表达数据集。