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      Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer

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      Author(s)
      Tokat, Unal Metin
      Tarman, Ibrahim Oguzhan
      Ersan, Pelin Gulizar
      Raza, Umar
      Saatci, O.
      Sahin, O.
      Ogul, H.
      Riazalhosseini, Y.
      Can, T.
      Assidicky, Ridho
      Date
      2022-03-25
      Source Title
      Breast Cancer Research and Treatment
      Print ISSN
      0167-6806
      Electronic ISSN
      1573-7217
      Publisher
      Springer New York LLC
      Volume
      193
      Issue
      2
      Pages
      331 - 348
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes. Methods Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings. Results We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients. Conclusion FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.
      Keywords
      TNBC
      miRNA-mRNA network
      Chemoresistance
      miR-326
      Fibronectin
      Integrin
      Hypoxia
      ECM stiffness
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      http://hdl.handle.net/11693/111244
      Published Version (Please cite this version)
      https://www.doi.org/10.1007/s10549-022-06569-5
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