Exosomes regulate doxorubicin resistance in breast cancer via miR-34a-5p/NOTCH1.

Breast cancer (BRCA) is the most common cancer among women. Adriamycin (ADR), also known as doxorubicin (Dox), is a commonly used chemotherapeutic agent for BRCA patients, however, the susceptibility of tumor cells to develop resistance to Dox has severely limited its clinical use. One new promising therapeutic target for breast cancer patients is exosomes. The objective of this study was to investigate the role of exosomes in regulating Dox resistance in BRCA. In this study, the exosomes from both types of cells were extracted by differential centrifugation. The effect of exosomes on drug resistance was assessed by laser confocal microscopy, MTT assay, and qRT-PCR. The miRNA was transfected into cells using Lipofectamine 2000, which was then evaluated for downstream genes and changes in drug resistance. Exosomes from MCF-7 cells (MCF-7/exo) and MCF-7/ADR cells (ADR/exo) were effectively extracted in this study. The ADR/exo was able to endocytose MCF-7 cells and make them considerably more resistant to Dox. Moreover, we observed a significant difference in miR-34a-5p expression in MCF-7/ADR and ADR/exo compared to MCF-7 and MCF-7/exo. Among the miR-34a-5p target genes, NOTCH1 displayed a clear change with a negative correlation. In addition, when miR-34a-5p expression was elevated in MCF-7/ADR cells, the expression of miR-34a-5p in ADR/exo was also enhanced alongside NOTCH1, implying that exosomes may carry miRNA into and out of cells and perform their function. In conclusion, exosomes can influence Dox resistance in breast cancer cells by regulating miR-34a-5p/NOTCH1. These findings provide novel insights for research into the causes of tumor resistance and the enhancement of chemotherapy efficacy in breast cancer.

Chen NN ，Zhou KF ，Miao Z ，Chen YX ，Cui JX ，Su SW ... -  《-》

[miR-34a may regulate sensitivity of breast cancer cells to adriamycin via targeting Notch1].

Li X ，Zhao J ，Tang J 《-》

MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1.

MicroRNA-34a (miR-34a) as a tumor suppressor has been reported in many other studies. However, its role in modulating the sensitivity of breast cancer cells to adriamycin (ADR) remains unclear. The aim of this study is to evaluate the role of miR-34a in the sensitivity of breast cancer cells to ADR. The role of miR-34a in breast cancer cells was detected using MTT assay, flow cytometry assay, real-time PCR and Western blot, etc. The association of miR-34a and Notch1 was analyzed by dual-luciferase reporter assay and Notch1-siRNA technology. Real-time PCR assay was performed to test the expression of miR-34a and Notch1 in 38 selective breast cancer tissue samples. Ectopic overexpression of miR-34a could sensitize MCF-7 breast cancer cells to ADR. MiR-34a mimic could inhibit the luciferase activity of the construct containing wild-type 3' UTR of Notch1 in MCF-7/ADR cells. Notch1-siRNA could partially reverse the effect of miR-34a inhibitor in inducing chemoresistance of MCF-7 cells to ADR. Further, there was an inverse association between Notch1 and miR-34a expression in breast cancer. Dysregulation of miR-34a plays critical roles in the acquired ADR resistance of breast cancer, at least in part via targeting Notch1.

Li XJ ，Ji MH ，Zhong SL ，Zha QB ，Xu JJ ，Zhao JH ，Tang JH ... -  《-》

β-Elemene Reverses Chemoresistance of Breast Cancer Cells by Reducing Resistance Transmission via Exosomes.

Currently, exosomes that act as mediators of intercellular communication are being researched extensively. Our previous studies confirmed that these exosomes contain microRNAs (miRNAs) that could alter chemo-susceptibility, which is partly attributed to the successful intercellular transfer of multidrug resistance (MDR)-specific miRNAs. We also confirmed that β-elemene could influence MDR-related miRNA expression and regulate the expression of the target genes PTEN and Pgp, which may lead to the reversal of the chemoresistant breast cancer (BCA) cells. We are the first to report these findings, and we propose the following logical hypothesis: β-elemene can mediate MDR-related miRNA expression in cells, thereby affecting the exosome contents, reducing chemoresistance transmission via exosomes, and reversing the drug resistance of breast cancer cells. MTT-cytotoxic, miRNA microarray, real-time quantitative PCR, Dual Luciferase Activity Assay, and Western blot analysis were performed to investigate the impact of β-elemene on the expression of chemoresistance specific miRNA and PTEN as well as Pgp in chemoresistant BCA exosomes. Drug resistance can be reversed by β-elemene related to exosomes. There were 104 differentially expressed miRNAs in the exosomes of two chemoresistant BCA cells: adriacin (Adr) - resistant MCF-7 cells (MCF-7/Adr) and docetaxel (Doc) - resistant MCF-7 cells (MCF-7/Doc) that underwent treatment. Of these, 31 miRNAs were correlated with the constant changes in the MDR. The expression of miR-34a and miR-452 can lead to changes in the characteristics of two chemoresistant BCA exosomes: MCF-7/Adr exosomes (A/exo) and MCF-7/Doc exosomes (D/exo). The PTEN expression affected by β-elemene was significantly increased, and the Pgp expression affected by β-elemene was significantly decreased in both cells and exosomes. β-elemene induced a significant increase in the apoptosis rate in both MCF-7/Doc and MCF-7/Adr cells. Drug resistance can be reversed by β-elemene, which can alter the expression of some MDR-related miRNAs, including PTEN and Pgp in MCF-7/Adr and MCF-7/Doc in cells. It can therefore affect the exosome contents and induce the reduction of resistance transmission via exosomes.

Zhang J ，Zhang HD ，Yao YF ，Zhong SL ，Zhao JH ，Tang JH ... -  《-》

Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

Yu DD ，Wu Y ，Zhang XH ，Lv MM ，Chen WX ，Chen X ，Yang SJ ，Shen H ，Zhong SL ，Tang JH ，Zhao JH ... -  《-》