Abstract
Breast cancer is the most prevalent type of malignancy in women worldwide. Taxanes (paclitaxel and docetaxel) are widely applied as first-line chemotherapeutic agents, while the therapeutic effect is seriously limited by the development of drug resistance. In the present study, we screened out several miRNAs dysregulated in taxanes-resistant breast cancer samples and confirmed that two miRNAs (miR-335-5p and let-7c-5p) played a major role in cell proliferation, apoptosis, and chemo-resistance. In addition, the weighted gene co-expression network analysis (WGCNA) for potential target genes of miR-335-5p and let-7c-5p identified three hub genes (CXCL9, CCR7, and SOCS1) with a positive relationship to taxanes-sensitivity. Further, target relationships between miR-335-5p and CXCL9, let-7c-5p and CCR7/SOCS1 were confirmed by dual-luciferase reporter assays. Importantly, the regulatory functions of CXCL9, CCR7, and SOCS1 on proliferation and chemoresistance were validated. In conclusion, our study shed light on clinical theragnostic relationships between miR-335-5p/CXCL9, let-7c-5p/CCR7/SOCS1 axes, and taxanes-resistance in breast cancer.
Highlights
Breast cancer is the most prevalent type of malignancy in women worldwide [1]
According to Response Evaluation Criteria in Solid Tumors (RECIST), patients received taxanes treatments were divided into taxanes-sensitive (n = 79) group and taxanes-resistant group (n = 16) (Table S5)
There is a significantly positive correlation between Gene significance (GS) and MM in the module. (F) Weight coefficient was calculated between pairwise genes in the yellow module and the hub genes were presented as different sizes of circles according to weight coefficient
Summary
The incidence rate of breast cancer among young women increases rapidly, which is due partly to earlier diagnosis by the development of detection technology. Acquired chemo-resistance is relatively more common in clinics, which means tumors initially sensitive to chemotherapeutic agents become more and more insensitive during the course of treatment [7]. What’s worse, once tumors manifest resistance to a specific drug, they often resist to a large-scale of other chemotherapeutic agents that are chemically and functionally unrelated. This phenomenon is summarized as multidrug resistance (MDR) [8]
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