TY  - JOUR
AU  - Shukla, Kirti
AU  - Sharma, Ashwini Kumar
AU  - Ward, Aoife
AU  - Will, Rainer
AU  - Hielscher, Thomas
AU  - Balwierz, Aleksandra
AU  - Breunig, Christian
AU  - Münstermann, Ewald
AU  - König, Rainer
AU  - Keklikoglou, Ioanna
AU  - Wiemann, Stefan
TI  - MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer.
JO  - Molecular oncology
VL  - 9
IS  - 6
SN  - 1574-7891
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2017-03539
SP  - 1106 - 1119
PY  - 2015
AB  - 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.
KW  - CCNE1 protein, human (NLM Chemicals)
KW  - Cyclin E (NLM Chemicals)
KW  - MIRN30 microRNA, human (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Oncogene Proteins (NLM Chemicals)
KW  - RNA, Neoplasm (NLM Chemicals)
KW  - TNF Receptor-Associated Death Domain Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25732226
C2  - pmc:PMC5528752
DO  - DOI:10.1016/j.molonc.2015.01.008
UR  - https://inrepo02.dkfz.de/record/127516
ER  -