Dataset Information

MicroRNA-30c-regulated HDAC9 mediates chemoresistance of breast cancer.

ABSTRACT:

Purpose

Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the mechanism of HDAC9's contribution to chemoresistance remains poorly understood. The aim of this study was to investigate the role of miR-30c-regulated HDAC9 in chemoresistance of breast cancer and to determine the potential of selective inhibition of HDAC9 in sensitizing resistant breast cancer cells to chemotherapy.

Methods

Expression levels of HDAC9 and miR-30c were measured in breast cancer cells and tissues using quantitative PCR analysis. The effect of selective inhibition of HDAC9 on sensitizing MDR cells to chemotherapy was assessed. MiR-30c/HDAC9 pathways' potential to mediate chemoresistance was analyzed.

Results

Our studies show that HDAC9 was significantly up-regulated in chemoresistant breast cancer cell lines compared to a chemosensitive cell line and was inversely correlated with the levels of miR-30c. MiR-30c mimics and HDAC9 inhibitors reversed the chemoresistance of multidrug-resistant breast cancer cells.

Conclusions

These results indicate that the mechanism of chemoresistance reversal with selective HDAC inhibition was partially realized by regulating miR-30c via directly targeting HDAC9. Our findings suggest that the miR-30c/HDAC9 signaling axis could be a novel and potential therapeutic target in chemoresistant breast cancer.

SUBMITTER: Liang Z

PROVIDER: S-EPMC7021558 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is increasing evidence that cancer recurrence and resistance to chemotherapy are linked to a subset of cancer stem cells. However, detecting these cells specifically and targeting them therapeutically remain challenging. As microRNAs (miRNAs) are emerging as key players in cancer biology, we set up to identify miRNAs involved in chemoresistance of breast cancer stem cells. In this study, we enriched populations of chemoresistant cancer stem cells from breast cancer and non-transformed breast cell lines using mammospheres. These mammospheres were treated or not with two chemoreagents, and we profiled surviving cells using miRNA microarray analysis. Comparison of the profiles from treated and untreated mammospheres as well as control and cancer cells yielded a six-miRNAs signature specific for chemoresistant stem cell-enriched subpopulations. From this signature miR-363-3p was found to be most highly overexpressed in various breast cancer cell lines and derived cancer stem cell-enriched populations, whereas non-tumorigenic cells had low levels. Inhibition of miR-363-3p was found to decrease cancer stem cell maintenance and tumorigenicity in vitro. Consistently, miR-363-3p downregulation decreased tumor growth and metastatization by human tumor cells transplanted in mice. Finally, miR363-3p levels in the sera of 38 breast cancer patients enrolled in a neoadjuvant trial correlated well with the response to the chemotherapeutic treatments. Altogether, miR363-3p was identified as a mediator of the breast cancer stem cell phenotype, and it may provide a predictor of the response to chemotherapy from a simple blood test, as well as a potential therapeutic approach for cancer stem cell targeting. This data set aims at identifying differentially expressed miRNAs in chemoresistant mammospheres, by the profiling of miRNA in MCF7 breast cancer cell-derived mammospheres selected to be resistant to 5 Fluorouracil (5FU) or Paclitaxel, as compared to unselected MCF7 mammospheres.