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

  • Preclinical study
  • Published:
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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.

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Data availability

Raw RNA-seq data analyzed in the current study have been made available on NCBI Sequence Read Archive with accession PRJNA607780. The small RNA-Seq data have also been deposited to the SRA with the submission ID: PRJNA806717.

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Acknowledgements

We are thankful to the members of the Ozgur Sahin laboratory for invaluable discussion and advice. We thank Jitao David Zhang for his help with RNA-sequencing data.

Funding

This work was supported by European Commission FP7 Marie Curie Career Integration Grant PCIG14-GA-2013-631149 (OS), the American Cancer Society Institutional Research Grant IRG-17-179-04 (OS), NIH Research Project Grants R01-CA267101 (OS) and 2P20GM109091-06 (OS), the scholarship from Higher Education Commission of Pakistan (UR), the scholarship from 2211/A TÜBİTAK Domestic PhD Scholarship Program (UMT), and Susan G. Komen Interdisciplinary Graduate Training to Eliminate Cancer Disparities (IGniTE-CD) GTDR17500160 (OzgeS). YR is a research scholar of Fonds de recherche du Québec—Santé (FRQS).

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey

    Ridho Assidicky, Unal Metin Tokat, Ibrahim Oguzhan Tarman, Pelin Gulizar Ersan & Umar Raza

  2. Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA

    Ozge Saatci & Ozgur Sahin

  3. Faculty of Computer Sciences, Østfold University College, NO-1757, Halden, Norway

    Hasan Ogul

  4. McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada

    Yasser Riazalhosseini

  5. Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada

    Yasser Riazalhosseini

  6. Department of Computer Engineering, Middle East Technical University, 06800, Ankara, Turkey

    Tolga Can

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  1. Ridho Assidicky
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Contributions

OS supervised the study. OS and UR conceptualized the study. RA, UMT, IOT, OzgeS, PG, and UR designed and performed the experiments, data acquisition, and data analysis. RA, UMT, IOT, OzgeS, and OS contributed to writing, review, and/or revision of the manuscript. HO and TC helped building the miRNA–mRNA network. YR oversaw RNA-seq and small RNA-seq experiments. All authors read and approved the final manuscript.

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Correspondence to Ozgur Sahin.

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Conflict of interest

O.S. is the co-founder and manager of OncoCube Therapeutics LLC and founder and president of LoxiGen, Inc. The other authors declare no potential conflict of interest.

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Assidicky, R., Tokat, U.M., Tarman, I.O. et al. Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer. Breast Cancer Res Treat 193, 331–348 (2022). https://doi.org/10.1007/s10549-022-06569-5

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