MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ breast cancer.
Biomarkers, Tumor
/ biosynthesis
Breast Neoplasms
/ drug therapy
Chromatin
/ genetics
DNA Methylation
Disease Progression
Drug Resistance, Neoplasm
Estrogen Receptor alpha
/ genetics
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
/ genetics
Humans
MCF-7 Cells
MicroRNAs
/ biosynthesis
Prognosis
Tamoxifen
/ pharmacology
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
24
05
2018
accepted:
15
01
2019
revised:
16
12
2018
pubmed:
21
2
2019
medline:
18
12
2019
entrez:
21
2
2019
Statut:
ppublish
Résumé
MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of MIR196A are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein. Genomic data and chromatin interaction analysis were used to discover functional promoter and enhancer elements for MIR196A. Expression data were used to associate MIR196A with mechanisms of resistance, breast cancer subtypes and prognosis. Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long-range transcriptional regulation between promoter and enhancer elements bound by ERα. Expression of this miRNA is significantly increased in drug-resistant models of hormone-receptor positive disease. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease. This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.
Sections du résumé
BACKGROUND
MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of MIR196A are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein.
METHODS
Genomic data and chromatin interaction analysis were used to discover functional promoter and enhancer elements for MIR196A. Expression data were used to associate MIR196A with mechanisms of resistance, breast cancer subtypes and prognosis.
RESULTS
Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long-range transcriptional regulation between promoter and enhancer elements bound by ERα. Expression of this miRNA is significantly increased in drug-resistant models of hormone-receptor positive disease. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease.
CONCLUSION
This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.
Identifiants
pubmed: 30783203
doi: 10.1038/s41416-019-0395-8
pii: 10.1038/s41416-019-0395-8
pmc: PMC6461839
doi:
Substances chimiques
Biomarkers, Tumor
0
Chromatin
0
Estrogen Receptor alpha
0
HOXA7 protein, human
0
HOXC10 protein, human
0
HOXC11 protein, human
0
Homeodomain Proteins
0
MIRN196 microRNA, human
0
MicroRNAs
0
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
621-632Subventions
Organisme : Cancer Research UK
Pays : United Kingdom
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