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

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...

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Autores principales: Schwarzenbacher, Daniela, Klec, Christiane, Pasculli, Barbara, Cerk, Stefanie, Rinner, Beate, Karbiener, Michael, Ivan, Cristina, Barbano, Raffaela, Ling, Hui, Wulf-Goldenberg, Annika, Stanzer, Stefanie, Rinnerthaler, Gabriel, Stoeger, Herbert, Bauernhofer, Thomas, Haybaeck, Johannes, Hoefler, Gerald, Jahn, Stephan Wenzel, Parrella, Paola, Calin, George Adrian, Pichler, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359814/
https://www.ncbi.nlm.nih.gov/pubmed/30709367
http://dx.doi.org/10.1186/s13058-019-1104-5
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author Schwarzenbacher, Daniela
Klec, Christiane
Pasculli, Barbara
Cerk, Stefanie
Rinner, Beate
Karbiener, Michael
Ivan, Cristina
Barbano, Raffaela
Ling, Hui
Wulf-Goldenberg, Annika
Stanzer, Stefanie
Rinnerthaler, Gabriel
Stoeger, Herbert
Bauernhofer, Thomas
Haybaeck, Johannes
Hoefler, Gerald
Jahn, Stephan Wenzel
Parrella, Paola
Calin, George Adrian
Pichler, Martin
author_facet Schwarzenbacher, Daniela
Klec, Christiane
Pasculli, Barbara
Cerk, Stefanie
Rinner, Beate
Karbiener, Michael
Ivan, Cristina
Barbano, Raffaela
Ling, Hui
Wulf-Goldenberg, Annika
Stanzer, Stefanie
Rinnerthaler, Gabriel
Stoeger, Herbert
Bauernhofer, Thomas
Haybaeck, Johannes
Hoefler, Gerald
Jahn, Stephan Wenzel
Parrella, Paola
Calin, George Adrian
Pichler, Martin
author_sort Schwarzenbacher, Daniela
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-019-1104-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-63598142019-02-07 MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors Schwarzenbacher, Daniela Klec, Christiane Pasculli, Barbara Cerk, Stefanie Rinner, Beate Karbiener, Michael Ivan, Cristina Barbano, Raffaela Ling, Hui Wulf-Goldenberg, Annika Stanzer, Stefanie Rinnerthaler, Gabriel Stoeger, Herbert Bauernhofer, Thomas Haybaeck, Johannes Hoefler, Gerald Jahn, Stephan Wenzel Parrella, Paola Calin, George Adrian Pichler, Martin Breast Cancer Res Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-019-1104-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-01 2019 /pmc/articles/PMC6359814/ /pubmed/30709367 http://dx.doi.org/10.1186/s13058-019-1104-5 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Schwarzenbacher, Daniela
Klec, Christiane
Pasculli, Barbara
Cerk, Stefanie
Rinner, Beate
Karbiener, Michael
Ivan, Cristina
Barbano, Raffaela
Ling, Hui
Wulf-Goldenberg, Annika
Stanzer, Stefanie
Rinnerthaler, Gabriel
Stoeger, Herbert
Bauernhofer, Thomas
Haybaeck, Johannes
Hoefler, Gerald
Jahn, Stephan Wenzel
Parrella, Paola
Calin, George Adrian
Pichler, Martin
MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title_full MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title_fullStr MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title_full_unstemmed MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title_short MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors
title_sort mir-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase cb, thereby sensitizing cells for pi3kinase inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359814/
https://www.ncbi.nlm.nih.gov/pubmed/30709367
http://dx.doi.org/10.1186/s13058-019-1104-5
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