MiR-21 plays a dual role in tumor formation and cytotoxic response in breast tumors

Tu Dan, Anuradha A. Shastri, Ajay Palagani, Simone Buraschi, Thomas Neill, Jason E. Savage, Aastha Kapoor, Tiziana Deangelis, Sankar Addya, Kevin Camphausen, Renato V. Iozzo, Nicole L. Simone

Research output: Contribution to journalArticlepeer-review

Abstract

Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21−/− mice, and grew in ~50% of miR-21+/− and 100% in miR-21+/+ mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21−/− mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio-and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients.

Original languageEnglish (US)
Article number888
Pages (from-to)1-16
Number of pages16
JournalCancers
Volume13
Issue number4
DOIs
StatePublished - Feb 2021

Keywords

  • Apoptosis
  • Breast cancer
  • Metastases
  • MiR-21

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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