Effects of Oestrogen on MicroRNA Expression in Hormone-Responsive Breast Cancer Cells
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Oestrogen receptor alpha (ERα) is a ligand-dependent transcription factor that mediates oestrogen effects in hormone-responsive cells. Following oestrogenic activation, ERα directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) represent a class of small noncoding RNAs that function as negative regulators of protein-coding gene expression. They are found aberrantly expressed or mutated in cancer, suggesting their crucial role as either oncogenes or tumour suppressor genes. Here, we analysed changes in miRNA expression in response to oestrogen in hormone-responsive breast cancer MCF-7 and ZR-75.1 cells by microarray-mediated expression profiling. This led to the identification of 172 miRNAs up- or down-regulated by ERα in response to 17β-oestradiol, of which 52 are similarly regulated by the hormone in the two cell models investigated. To identify mechanisms by which ERα exerts its effects on oestrogen-responsive miRNA genes, the oestrogen-dependent miRNA expression profiles were integrated with global in vivo ERα binding site mapping in the genome by ChIP-Seq. In addition, data from miRNA and messenger RNA (mRNA) expression profiles obtained under identical experimental conditions were compared to identify relevant miRNA target transcripts. Results show that miRNAs modulated by ERα represent a novel genomic pathway to impact oestrogen-dependent processes that affect hormone-responsive breast cancer cell behaviour. MiRNome analysis in tumour tissues from breast cancer patients confirmed a strong association between expression of these small RNAs and clinical outcome of the disease, although this appears to involve only marginally the oestrogen-regulated miRNAs identified in this study.
KeywordsOestrogen receptor Breast cancer MicroRNA Cell cycle Gene expression
The authors thank Rosario Casale and Maria Francesca Papa for technical assistance and Claudio Scafoglio for critically reading the revised manuscript. Work supported by: European Union (CRESCENDO I.P., contract number LSHM-CT2005-018652), Italian Association for Cancer Research (grant IG-8586), Ministry for Education, University and Research (grants PRIN 2008CJ4SYW_004) and University of Salerno (Fondi FARB 2011). CC, FR, GN and RT are fellows of Fondazione con il Sud, MR is supported by a ‘Vladimir Ashkenazy’ fellowship of Italian Association for Cancer Research, MRDF is PhD student of the Research Doctorate ‘Computational Biology and Bioinformatics’ of the University of Napoli ‘Federico II’ supported by Fondazione IRCCS SDN, FC is PhD student of the Research Doctorate ‘Molecular Pathology and Physiopathology’ of the University of Napoli ‘Federico II’, GG and SS are PhD students of the Research Doctorate ‘Experimental Physiopathology and Neurosciences’ of the Second University of Napoli and CS is PhD student of the Research Doctorate ‘Molecular Oncology, Experimental Immunology and Innovative Therapy Development’ of the ‘Magna Graecia’ University of Catanzaro.
Conflict of interest
The authors declare that they have no conflict of interest.
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