Journal
BREAST CANCER RESEARCH
Volume 21, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13058-019-1104-5
Keywords
Non-coding RNA; microRNAs; Breast cancer
Categories
Funding
- Austrian Society of Hematology and Medical Oncology
- National Institutes of Health (NIH/NCATS) through the NIH Common Fund, Office of Strategic Coordination (OSC) [UH3TR00943-01]
- NIH/NCI [1 R01 CA182905-01]
- U54 grant - UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project
- Team DOD grant [CA160445P1]
- CLL Moonshot Flagship project
- Ladies Leukemia League grant
- Oesterreichische Nationalbank [14869]
- Pfizer
- Verein fur Krebskranke
- Italian Ministry of Health (MoH)
- European Regional Development Fund A way of making Europe under the TRANSCAN ERA-NET on Translational Cancer Research [RRC-2014-2354565, CANCER13-FP-011]
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG-1269/2006]
- Estate of C. G. Johnson, Jr.
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BackgroundNon-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.MethodsIn 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.ResultsAmong 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.ConclusionOur 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.
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