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

Abstract

PurposeTriple-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).MethodsEVs 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.ResultsMCF10A 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.ConclusionEVs 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 materialThe online version of this article (10.1007/s10549-018-4925-5) contains supplementary material, which is available to authorized users.

Total Blood Exosomes in Breast Cancer: Potential Role in Crucial Steps of Tumorigenesis

“…It was shown that EVs isolated from the triple-negative breast cancer cells HCC1806 were capable to induce the proliferation and drug resistance of the non-tumorigenic MCF10A breast cells. MiRNA profiling in the recipient cells suggested that these phenotypes could be mediated by changes in the expression of miRNAs associated with proliferation, apoptosis, invasion, and migration [ 40 ]. Moreover, earlier it was found that exosomes from ovarian cancer cells SKOV-3 and OVCAR-3 promoted mesenchymal stem cell and endothelial cell migration in a time- and concentration-dependent manner [ 41 ].…”

Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance

“…In addition, platelet-derived growth factor receptor-beta (PDGFR-β), which is enriched in EVs released by melanoma cells resistant to BRAF inhibitor, PLX4720, can be transferred to recipient melanoma cells, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from BRAF inhibition [104]. More recently, triple negative breast cancer cell lines resistant to Docetaxel and Doxorubicin were shown to release EVs that induced resistance to these chemotherapy drugs in recipient non-tumorigenic breast cells [105]. Indeed, these EVs caused changes in gene expression associated with cell proliferation and apoptosis including the PI3K/AKT pathway, suggesting that they may contain ligands or receptors connected to the PI3K signaling axis [105].…”

“…More recently, triple negative breast cancer cell lines resistant to Docetaxel and Doxorubicin were shown to release EVs that induced resistance to these chemotherapy drugs in recipient non-tumorigenic breast cells [105]. Indeed, these EVs caused changes in gene expression associated with cell proliferation and apoptosis including the PI3K/AKT pathway, suggesting that they may contain ligands or receptors connected to the PI3K signaling axis [105]. Likewise, EVs can also carry prosurvival molecules that modulate the immune system functions likely inducing immune tolerance and escape.…”

Exosomes and breast cancer drug resistance

“…To date, several large-scale validation studies were performed to determine the exosomal protein and miRNA expression profiles in BC after chemotherapy [44][45][46][47][48] . These studies would provide a comprehensive understanding of the function of dysregulated exosomal miRNAs and proteins, which might be helpful to understand the transmission of chemoresistance mediated by exosomes and to overcome chemoresistance in BC treatment.…”