Chemotherapy-Induced Extracellular Vesicle miRNAs Promote Breast Cancer Stemness by Targeting ONECUT2

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 14; pp. 3608 - 3621
• Main Authors: Shen, Meng, Dong, Chuan, Ruan, Xianhui, Yan, Wei, Cao, Minghui, Pizzo, Donald, Wu, Xiwei, Yang, Lin, Liu, Liang, Ren, Xiubao, Wang, Shizhen Emily
• Format: Journal Article
• Language: English
• Published: United States 15.07.2019
• Subjects: Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Docetaxel - pharmacology; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Extracellular Vesicles - drug effects; Extracellular Vesicles - genetics; Extracellular Vesicles - pathology; Female; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Transcription Factors - genetics; Transcription Factors - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-4055

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 , and . 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. SIGNIFICANCE: 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.