siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE
    • Publication Information:
      Publication: London, UK : BioMed Central Ltd
      Original Publication: London, UK : Current Science, c1999-
    • Subject Terms:
      Drug Resistance, Neoplasm*/genetics ; Breast Neoplasms*/pathology ; Breast Neoplasms*/genetics ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/drug therapy ; Breast Neoplasms*/mortality ; Breast Neoplasms*/therapy ; Enhancer of Zeste Homolog 2 Protein*/metabolism ; Enhancer of Zeste Homolog 2 Protein*/genetics ; Gene Expression Regulation, Neoplastic* ; Epithelial-Mesenchymal Transition*/genetics ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; RNA, Small Interfering*/genetics ; Xenograft Model Antitumor Assays*; Humans ; Female ; Animals ; Mice ; Cell Line, Tumor ; Disease Progression ; MCF-7 Cells ; Cell Proliferation ; Gene Expression Profiling
    • Abstract:
      Background: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets.
      Methods: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells. Clinical relevance of the key genes was determined using Kaplan-Meier survival analyses on The Cancer Genome Atlas dataset of breast cancer patients. Gene overexpression/knockdown, spheroid formation, flow cytometric analysis, chromatin immunoprecipitation, immunocytochemistry, wound healing/transwell migration assays, and cancer stem cell transcription factor activation profiling array were used to elucidate the regulatory mechanism of integrin α11 expression. Tumour-bearing xenograft models were used to demonstrate integrin α11 is a potential therapeutic target.
      Results: Integrin α11 was consistently upregulated in drug-resistant breast cancer cells, and its silencing inhibited cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) while restoring sensitivity to anticancer drugs. HIF1α, GLI-1, and EZH2 contributed the most to the regulation of integrin α11 and EZH2 expression, with EZH2 being more necessary for EZH2 autoinduction than HIF1α and GLI-1. Additionally, unlike HIF1α or EZH2, GLI-1 was the sole transcription factor activated by integrin-linked focal adhesion kinase, indicating GLI-1 as a key driver of the EZH2-integrin α11 axis operating for cancer stem cell survival and EMT. Kaplan-Meier survival analysis using The Cancer Genome Atlas (TCGA) dataset also revealed both EZH2 and integrin α11 could be strong prognostic factors of relapse-free and overall survival in breast cancer patients. However, the superior efficacy of integrin α11 siRNA therapy over EZH2 siRNA treatment was demonstrated by enhanced inhibition of tumour growth and prolonged survival in murine models bearing tumours.
      Conclusion: Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.
      (© 2024. The Author(s).)
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    • Grant Information:
      NRF-2020R1A2C2005690 and NRF-2023R1A2C1006689 National Research Foundation of Korea
    • Contributed Indexing:
      Keywords: Cancer stem cells; Drug resistant breast cancer; EZH2; Epithelial-mesenchymal transition; GLI-1; HIF1α; Integrin α11
    • Accession Number:
      EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
      EC 2.1.1.43 (EZH2 protein, human)
      0 (RNA, Small Interfering)
    • Publication Date:
      Date Created: 20240425 Date Completed: 20240426 Latest Revision: 20240429
    • Publication Date:
      20240429
    • Accession Number:
      PMC11046805
    • Accession Number:
      10.1186/s13058-024-01827-4
    • Accession Number:
      38664825