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Regulation of NF-κB signaling and cell cycle progression by microRNA-30c-2-3p in breast cancer

Shukla, Kirti

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Abstract

NF-κB signaling is frequently deregulated in a variety of cancers and is constitutively active in estrogen receptor negative breast cancer subtypes. These molecular subtypes of breast cancer are associated with poor overall survival. During my PhD work, I focused on mechanisms of NF-κB regulation in breast cancer by miRNAs, key regulators of eukaryotic gene expression, which bind their target mRNAs via seed sequences and inhibit gene expression at the post transcriptional level. In a previous study, miR-30c-2-3p was found to be one of the strongest negative regulators of NF-κB signaling in a genome-wide miRNA screen. I uncovered the underlying molecular mechanisms by which miR-30c-2-3p regulates NF-κB signaling and cell cycle progression in breast cancer by combining in vitro data with publically available breast cancer patient datasets. I could show that miR-30c-2-3p directly targets TRADD, an adaptor protein of the TNFR/NF-κB signaling pathway as well as the cell cycle protein, CCNE1. Ectopic expression of miR-30c-2-3p downregulated essential cytokines IL8, IL6 and CXCL1, reduced cell proliferation, and invasion in MDA-MB-231 breast cancer cells. RNAi-induced silencing of TRADD phenocopied the effects on invasion and cytokine expression also observed with miR-30c-2-3p, while inhibition of CCNE1 phenocopied the effects of the miRNA on cell proliferation. The tumor suppressive role of miR-30c-2-3p was confirmed in a cohort of 781 breast tumors with matched mRNA and miRNA expression data where higher expression of miR-30c-2-3p was associated with better survival. Furthermore an anticorrelation with expression of target genes and miR-30c-2-3p was seen in these breast cancer patients. These findings are important in the context of breast cancer where NF-κB signaling has been implicated to play a role in tumor initiation, progression, metastasis and resistance to chemotherapy. During my thesis work I could establish that miR-30c-2-3p negatively regulates both NF-κB signaling and cell cycle progression, that are two important signaling pathways frequently deregulated in breast cancer. As a result, miR-30c-2-3p directly effects several hallmarks of cancer cells, i.e., proliferation, expression of inflammatory cytokines as well as invasion, and can be potentially used for therapeutic intervention in miRNA based cancer therapy.

Item Type: Dissertation
Supervisor: Wiemann, Prof. Dr. Stefan
Date of thesis defense: 5 November 2014
Date Deposited: 17 Nov 2014 09:45
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Controlled Keywords: TRADD, TNFR/NF-κB signaling, RNAi
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