MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

Ward, A.
Shukla, K.
Balwierz, A.
Soons, Z.
König, R.
Sahin, O.
Wiemann, S.
Source Title
Journal of Pathology
Print ISSN
Electronic ISSN
John Wiley and Sons Ltd
368 - 379
Journal Title
Journal ISSN
Volume Title

Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.

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Book Title
Breast cancer, C19MC cluster, Cell cycle network, MicroRNAs, Tamoxifen resistance, Estrogen receptor alpha, MicroRNA, Microrna 519a, Phosphatidylinositol 3 kinase, Small untranslated RNA, Tamoxifen, Unclassified drug, Algorithm, Apoptosis, Article, Breast cancer, Cell cycle progression, Cell viability, Controlled study, Correlation analysis, Disease specific survival, Estrogen receptor positive breast cancer, Gain of function mutation, Gene control, Gene expression, Gene targeting, Human, Human cell, Loss of function mutation, Nucleotide sequence, Priority journal, Tumor suppressor gene, Breast cancer, C19MC cluster, Cell cycle network, MicroRNAs, Tamoxifen resistance, Antineoplastic Agents, Hormonal, Apoptosis, Breast Neoplasms, Cell Cycle, Cell Line, Tumor, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, MicroRNAs, Pharmacogenetics, Phosphatidylinositol 3-Kinases, Signal Transduction, Tamoxifen, Tumor Markers, Biological
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