Extracellular vesicles from triple-negative breast cancer cells promote proliferation and drug resistance in non-tumorigenic breast cells

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Abstract

Purpose

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, is genetically heterogeneous which challenges the identification of clinically effective molecular makers. Extracellular vesicles (EVs) are key players in the intercellular signaling communication and have been shown to be involved in tumorigenesis. The main goal of this study was to evaluate the role and mechanisms of EVs derived from TNBC cells in modulating proliferation and cytotoxicity to chemotherapeutic agents in non-tumorigenic breast cells (MCF10A).

Methods

EVs were isolated from TNBC cell lines and characterized by nanoparticle tracking analysis, Western blot, and transmission electron microscopy. MCF10A cells were treated with the isolated EVs and evaluated for cell proliferation and cytotoxicity to Docetaxel and Doxorubicin by the MTT and MTS assays, respectively. Gene and miRNA expression profiling was performed in the treated cells to determine expression changes that may be caused by EVs treatment.

Results

MCF10A cells treated with HCC1806-EVs (MCF10A/HCC1806-EVs) showed a significant increase in cell proliferation and resistance to the therapeutic agents tested. No significant effects were observed in the MCF10A cells treated with EVs derived from MDA-MB-231 cells. Gene and miRNA expression profiling revealed 138 genes and 70 miRNAs significantly differentially expressed among the MCF10A/HCC1806-EVs and the untreated MCF10A cells, affecting mostly the PI3K/AKT, MAPK, and HIF1A pathways.

Conclusion

EVs isolated from the HCC1806 TNBC cells are capable of inducing proliferation and drug resistance on the non-tumorigenic MCF10A breast cells, potentially mediated by changes in genes and miRNAs expression associated with cell proliferation, apoptosis, invasion, and migration.

Electronic supplementary material

The online version of this article (10.1007/s10549-018-4925-5) contains supplementary material, which is available to authorized users.

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Most cited references 18

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Functional microRNA targets in protein coding sequences.

Martin Reczko, Manolis Maragkakis, Panagiotis Alexiou … (2012)

Experimental evidence has accumulated showing that microRNA (miRNA) binding sites within protein coding sequences (CDSs) are functional in controlling gene expression. Here we report a computational analysis of such miRNA target sites, based on features extracted from existing mammalian high-throughput immunoprecipitation and sequencing data. The analysis is performed independently for the CDS and the 3(')-untranslated regions (3(')-UTRs) and reveals different sets of features and models for the two regions. The two models are combined into a novel computational model for miRNA target genes, DIANA-microT-CDS, which achieves higher sensitivity compared with other popular programs and the model that uses only the 3(')-UTR target sites. Further analysis indicates that genes with shorter 3(')-UTRs are preferentially targeted in the CDS, suggesting that evolutionary selection might favor additional sites on the CDS in cases where there is restricted space on the 3(')-UTR.

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Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin.

Olga Kovalchuk, Jody Filkowski, James Meservy … (2008)

Many chemotherapy regiments are successfully used to treat breast cancer; however, often breast cancer cells develop drug resistance that usually leads to a relapse and worsening of prognosis. We have shown recently that epigenetic changes such as DNA methylation and histone modifications play an important role in breast cancer cell resistance to chemotherapeutic agents. Another mechanism of gene expression control is mediated via the function of small regulatory RNA, particularly microRNA (miRNA); its role in cancer cell drug resistance still remains unexplored. In the present study, we investigated the role of miRNA in the resistance of human MCF-7 breast adenocarcinoma cells to doxorubicin (DOX). Here, we for the first time show that DOX-resistant MCF-7 cells (MCF-7/DOX) exhibit a considerable dysregulation of the miRNAome profile and altered expression of miRNA processing enzymes Dicer and Argonaute 2. The mechanistic link of miRNAome deregulation and the multidrug-resistant phenotype of MCF-7/DOX cells was evidenced by a remarkable correlation between specific miRNA expression and corresponding changes in protein levels of their targets, specifically those ones that have a documented role in cancer drug resistance. Furthermore, we show that microRNA-451 regulates the expression of multidrug resistance 1 gene. More importantly, transfection of the MCF-7/DOX-resistant cells with microRNA-451 resulted in the increased sensitivity of cells to DOX, indicating that correction of altered expression of miRNA may have significant implications for therapeutic strategies aiming to overcome cancer cell resistance.

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Is Open Access

Exosome-mediated breast cancer chemoresistance via miR-155 transfer

Juliana Santos, Natália Lima, Luis Sarian … (2018)

Breast cancer remains the most prevalent cause of cancer mortality in woman worldwide due to the metastatic process and therapy resistance. Resistance against cancer therapy is partially attributed to cancer stem cells (CSCs). These cells arise from epithelial cells undergoing epithelial-to-mesenchymal transition (EMT) and might be responsible for tumor recurrence. In this study, we reported the relevance of miR-155 upregulation in chemoresistant cells associated with EMT. Notably, we found miR-155 induction in exosomes isolated from CSCs and resistant cells, followed by resistant cells’ exosome transfer to the recipient sensitive cells. Functionally, miR-155 mimic assay showed an enrichment in miR-155 from exosome concomitant with miR-155 exosome transfer to breast cancer cells. In parallel to these effects, we also observed EMT change in miR-155 transfected cells. The chemoresistance phenotype transfer to sensitive cells and the migration capability was analyzed by MTT and scratch assays and our results suggest that exosomes may intermediate resistance and migration capacity to sensitive cells partly through exosome transfer of miR-155. Taken together, our findings establish the significance of exosome-mediate miR-155 chemoresistance in breast cancer cells, with implications for targeting miR-155 signaling as a possible therapeutic strategy.

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Author and article information

Contributors

Luciane Regina Cavalli:

ORCID: http://orcid.org/0000-0001-5619-9037

lrc@georgetown.edu

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res. Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 1 September 2018

Publication date PMC-release: 1 September 2018

Publication date (Print): 2018

Volume: 172

Issue: 3

Pages: 713-723

Affiliations

[1 ]ISNI 0000 0001 2186 0438, GRID grid.411667.3, Department of Oncology, Lombardi Comprehensive Cancer Center, , Georgetown University Medical Center, ; Washington, DC USA

[2 ]ISNI 0000 0001 1941 472X, GRID grid.20736.30, Department of Genetics, , Federal University of Paraná, ; Curitiba, PR Brazil

[3 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Faculty of Pharmacy, , King Abdulaziz University, ; Jeddah, Saudi Arabia

Author information

Patricia Midori Murobushi Ozawa http://orcid.org/0000-0002-7992-143X

Luciane Regina Cavalli http://orcid.org/0000-0001-5619-9037

Article

Publisher ID: 4925

DOI: 10.1007/s10549-018-4925-5

PMC ID: 6245099

PubMed ID: 30173296

SO-VID: 2584263c-445c-4752-b13a-094d1bed18fb

License:

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.

History

Date received : 3 July 2018

Date accepted : 17 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;

Award ID: 88881.136048/2017-01

Award Recipient : Patricia Midori Murobushi Ozawa

Funded by: FundRef http://dx.doi.org/10.13039/100008064, Georgetown University;

Funded by: FundRef http://dx.doi.org/10.13039/501100004612, Fundação Araucária;

Award ID: CP 01/16 – PPSUS

Award ID: PRONEX

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tnbc,exosomes,proliferation,drug resistance,gene expression,mirna expression

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tnbc, exosomes, proliferation, drug resistance, gene expression, mirna expression

Extracellular vesicles from triple-negative breast cancer cells promote proliferation and drug resistance in non-tumorigenic breast cells

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Abstract

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Methods

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Conclusion

Electronic supplementary material

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Journal of Circulating Biomarkers

Most cited references 18

Functional microRNA targets in protein coding sequences.

Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin.

Exosome-mediated breast cancer chemoresistance via miR-155 transfer

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