MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors.
Animals
Breast
/ pathology
Carcinogenesis
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Down-Regulation
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mice
Mice, Nude
MicroRNAs
/ metabolism
Middle Aged
Neoplastic Stem Cells
/ drug effects
Oligonucleotide Array Sequence Analysis
Prognosis
Survival Analysis
Triple Negative Breast Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Breast cancer
Non-coding RNA
microRNAs
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
20
09
2018
accepted:
18
01
2019
entrez:
3
2
2019
pubmed:
3
2
2019
medline:
23
7
2019
Statut:
epublish
Résumé
Non-coding RNAs and especially microRNAs have been discovered to act as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet functionally uncharacterized microRNAs in human breast carcinogenesis. In an unbiased approach, we utilized an established model system for breast cancer (BC) stem cell formation ("mammosphere assay") to identify whole miRNome alterations in breast carcinogenesis. Clinical samples of BC patients were used to evaluate the human relevance of the newly identified miRNA candidates. One promising candidate, miR-1287-5p, was further explored on its impact on several hallmarks of cancer. The molecular mode of action was characterized by whole transcriptome analysis, in silico prediction tools, miRNA-interaction assays, pheno-copy assays, and drug sensitivity assays. Among several other microRNAs, miR-1287-5p was significantly downregulated in mammospheres and human BC tissue compared to normal breast tissue (p < 0.0001). Low expression levels were significantly associated with poor prognosis in BC patients. MiR-1287-5p significantly decreased cellular growth, cells in S phase of cell cycle, anchorage-independent growth, and tumor formation in vivo. In addition, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a novel prognostic factor in BC. Finally, PI3Kinase pathway chemical inhibitors combined with miR-1287-5p mimic increased the pharmacological growth inhibitory potential in triple negative BC cells. Our data identified for the first time the involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in difficult to treat triple negative BC.
Sections du résumé
BACKGROUND
Non-coding RNAs and especially microRNAs have been discovered to act as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet functionally uncharacterized microRNAs in human breast carcinogenesis.
METHODS
In an unbiased approach, we utilized an established model system for breast cancer (BC) stem cell formation ("mammosphere assay") to identify whole miRNome alterations in breast carcinogenesis. Clinical samples of BC patients were used to evaluate the human relevance of the newly identified miRNA candidates. One promising candidate, miR-1287-5p, was further explored on its impact on several hallmarks of cancer. The molecular mode of action was characterized by whole transcriptome analysis, in silico prediction tools, miRNA-interaction assays, pheno-copy assays, and drug sensitivity assays.
RESULTS
Among several other microRNAs, miR-1287-5p was significantly downregulated in mammospheres and human BC tissue compared to normal breast tissue (p < 0.0001). Low expression levels were significantly associated with poor prognosis in BC patients. MiR-1287-5p significantly decreased cellular growth, cells in S phase of cell cycle, anchorage-independent growth, and tumor formation in vivo. In addition, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a novel prognostic factor in BC. Finally, PI3Kinase pathway chemical inhibitors combined with miR-1287-5p mimic increased the pharmacological growth inhibitory potential in triple negative BC cells.
CONCLUSION
Our data identified for the first time the involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in difficult to treat triple negative BC.
Identifiants
pubmed: 30709367
doi: 10.1186/s13058-019-1104-5
pii: 10.1186/s13058-019-1104-5
pmc: PMC6359814
doi:
Substances chimiques
MIRN1287 microRNA, human
0
MicroRNAs
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CB protein, human
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
20Subventions
Organisme : NCATS NIH HHS
ID : UH3TR00943-01
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA182905-01
Pays : United States
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