%0 Journal Article
%A Shukla, Kirti
%A Sharma, Ashwini Kumar
%A Ward, Aoife
%A Will, Rainer
%A Hielscher, Thomas
%A Balwierz, Aleksandra
%A Breunig, Christian
%A Münstermann, Ewald
%A König, Rainer
%A Keklikoglou, Ioanna
%A Wiemann, Stefan
%T MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer.
%J Molecular oncology
%V 9
%N 6
%@ 1574-7891
%C Amsterdam [u.a.]
%I Elsevier
%M DKFZ-2017-03539
%P 1106 - 1119
%D 2015
%X Nuclear Factor kappa B (NF-κB) signaling is frequently deregulated in a variety of cancers and is constitutively active in estrogen receptor negative (ER-) breast cancer subtypes. These molecular subtypes of breast cancer are associated with poor overall survival. We focused on mechanisms of NF-κB regulation by microRNAs (miRNAs), which regulate eukaryotic gene expression at the post-transcriptional level. In a previous genome-wide miRNA screen, we had identified miR-30c-2-3p as one of the strongest negative regulators of NF-κB signaling. Here we have uncovered the underlying molecular mechanisms and its consequences in breast cancer. In vitro results show that miR-30c-2-3p directly targets both TNFRSF1A-associated via death domain (TRADD), an adaptor protein of the TNFR/NF-κB signaling pathway, and the cell cycle protein Cyclin E1 (CCNE1). Ectopic expression of miR-30c-2-3p downregulated essential cytokines IL8, IL6, CXCL1, and reduced cell proliferation as well as invasion in MDA-MB-231 breast cancer cells. RNA interference (RNAi) induced silencing of TRADD phenocopied the effects on invasion and cytokine expression caused by miR-30c-2-3p, while inhibition of CCNE1 phenocopied the effects on cell proliferation. We further confirmed the tumor suppressive role of this miRNA using a dataset of 781 breast tumors, where higher expression was associated with better survival in breast cancer patients. In summary we have elucidated the mechanism by which miR-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression in breast cancer.
%K CCNE1 protein, human (NLM Chemicals)
%K Cyclin E (NLM Chemicals)
%K MIRN30 microRNA, human (NLM Chemicals)
%K MicroRNAs (NLM Chemicals)
%K NF-kappa B (NLM Chemicals)
%K Oncogene Proteins (NLM Chemicals)
%K RNA, Neoplasm (NLM Chemicals)
%K TNF Receptor-Associated Death Domain Protein (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25732226
%2 pmc:PMC5528752
%R 10.1016/j.molonc.2015.01.008
%U https://inrepo02.dkfz.de/record/127516