American Association for Cancer Research
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Figure S4 from Chemotherapy-Induced Extracellular Vesicle miRNAs Promote Breast Cancer Stemness by Targeting ONECUT2

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journal contribution
posted on 2023-03-31, 02:44 authored by Meng Shen, Chuan Dong, Xianhui Ruan, Wei Yan, Minghui Cao, Donald Pizzo, Xiwei Wu, Lin Yang, Liang Liu, Xiubao Ren, Shizhen Emily Wang

Figure S4 showing effect of chemo-EVs on other ONECUT family members and ONECUT2 target genes

Funding

California Breast Cancer Research Program

Breast Cancer Research Foundation

American Association for Cancer Research

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ARTICLE ABSTRACT

Cancer-secreted, extracellular vesicle (EV)–encapsulated miRNAs enable cancer cells to communicate with each other and with noncancerous cells in tumor pathogenesis and response to therapies. Here, we show that treatment with a sublethal dose of chemotherapeutic agents induces breast cancer cells to secrete EV with the capacity to stimulate a cancer stem-like cell (CSC) phenotype, rendering cancer cells resistance to therapy. Chemotherapy induced breast cancer cells to secrete multiple EV miRNAs, including miR-9-5p, miR-195-5p, and miR-203a-3p, which simultaneously targeted the transcription factor One Cut Homeobox 2 (ONECUT2), leading to induction of CSC traits and expression of stemness-associated genes, including NOTCH1, SOX9, NANOG, OCT4, and SOX2. Inhibition of these miRNAs or restoration of ONECUT2 expression abolished the CSC-stimulating effect of EV from chemotherapy-treated cancer cells. In mice bearing xenograft mammary tumors, docetaxel treatment caused elevations of miR-9-5p, miR-195-5p, and miR-203a-3p in circulating EV and decreased ONECUT2 expression and increased levels of stemness-associated genes. These effects following chemotherapy were diminished in tumors deficient in exosome secretion. In human breast tumors, neoadjuvant chemotherapy decreased ONECUT2 expression in tumor cells. Our results indicate a mechanism by which cancer cells communicate with each other and self-adapt to survive in response to cytotoxic treatment. Targeting these adaptation mechanisms along with chemotherapy, such as by blocking the EV miRNA–ONECUT2 axis, represents a potential strategy to maximize the anticancer effect of chemotherapy and to reduce chemoresistance in cancer management. These findings reveal a critical mechanism of resistance to chemotherapy by which breast cancer cells secrete miRNA-containing extracellular vesicles to stimulate cancer stem cell-like features.

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