Abstract
Triple-negative breast cancer (TNBC) refers to breast cancer that does not have receptors for estrogen, progesterone, and HER2 protein. TNBC accounts for 10–20% of all cases of breast cancers and is characterized by its metastatic aggressiveness, poor prognosis, and limited treatment options. Here, we show that the metastatic nature of TNBC is critically regulated by a functional link between miR-200a and the transcription factor ELK3. We found that the expression levels of miR-200a and the ELK3 mRNA were negatively correlated in the luminal and TNBC subtypes of breast cancer cells. In vitro experiments revealed that miR-200a directly targets the 3’ untranslated region (UTR) of the ELK3 mRNA to destabilize the transcripts. Furthermore, ectopic expression of miR-200a impaired the migration and invasion of TNBC cells by reducing the expression level of the ELK3 mRNA. In in vivo studies, transfection of MDA-MB 231 cells (a claudin-low TNBC cell type) with exogenous miR-200a reduced their extravasation into the lung during 48 h after tail vein injection, and co-transfection of the cells with an expression plasmid harboring ELK3 that lacked an intact 3’UTR recovered their extravasation ability. Overall, our findings provide evidences that miR-200a and ELK3 is functionally linked to regulate invasive characteristics of breast cancers.
Highlights
Post-transcriptional modification of mRNAs is crucial for gene regulatory mechanisms and plays an important role in the control of carcinogenesis by regulating the expression of oncogenes and tumor suppressor genes [1]
We showed previously that the expression levels of the ELK3 mRNA and protein differ between subtypes of breast cancer; ELK3 expression is higher in the aggressive claudin-low type of triple-negative breast cancer (TNBC) than in the luminal type [18]
We found that CpG islands located in the first intron of the ELK3 gene were more highly methylated in MCF7 cells than in MDA-MB 231 cells, the ELK3 mRNA level in MCF7 cells was not increased by treatment with 5’-azacytidine at a concentration known to induce the transcription of other methylated genes, such as BRF2 [29]
Summary
Post-transcriptional modification of mRNAs is crucial for gene regulatory mechanisms and plays an important role in the control of carcinogenesis by regulating the expression of oncogenes and tumor suppressor genes [1]. Untranslated regions (UTRs), which are often referred to as cis-acting elements to regulate gene expression at post-transcriptional stage [2]. After being regarded as accessory sequences for a long time, accumulating evidences show that UTRs control mRNA stability, localization, and translation efficiency [3]. The sequences of 3’-UTR have been reported to play a pivotal role to control the stability of mRNA by being targeted by trans-acting factors including miRNAs [4]. MicroRNAs (miRNAs) are ~22 nucleotide-long RNA molecules that control gene expression by targeting 3’UTRs to destabilize mRNAs or inhibit their translation [5]. The role of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) in epithelial to mesenchymal transition (EMT) and metastasis formation
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