MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors

Daniela Schwarzenbacher, Christiane Klec, Barbara Pasculli, Stefanie Cerk, Beate Rinner, Michael Karbiener, Cristina Ivan, Raffaela Barbano, Hui Ling, Annika Wulf-Goldenberg, Stefanie Stanzer, Gabriel Rinnerthaler, Herbert Stoeger, Thomas Bauernhofer, Johannes Haybaeck, Gerald Hoefler, Stephan Wenzel Jahn, Paola Parrella, George Adrian Calin, Martin Pichler

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Abstract

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.

Original languageEnglish
Article number20
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
Publication statusPublished - Feb 1 2019

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Keywords

  • Breast cancer
  • microRNAs
  • Non-coding RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Schwarzenbacher, D., Klec, C., Pasculli, B., Cerk, S., Rinner, B., Karbiener, M., Ivan, C., Barbano, R., Ling, H., Wulf-Goldenberg, A., Stanzer, S., Rinnerthaler, G., Stoeger, H., Bauernhofer, T., Haybaeck, J., Hoefler, G., Jahn, S. W., Parrella, P., Calin, G. A., & Pichler, M. (2019). MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors. Breast Cancer Research, 21(1), [20]. https://doi.org/10.1186/s13058-019-1104-5