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Review Open Access

Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)

  • Authors:
    • Rigude Bu
    • Liu Bo
  • View Affiliations / Copyright

    Affiliations: Department of Thyroid Breast Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
    Copyright: © Bu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 151
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    Published online on: March 2, 2026
       https://doi.org/10.3892/ol.2026.15504
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Abstract

Triple‑negative breast cancer (TNBC), characterized by its aggressive nature and poor prognosis, exhibits a pronounced propensity for organ‑specific metastasis, which remains the primary cause of treatment failure and mortality. The present review synthesizes current knowledge on the pivotal role of microRNAs (miRNAs/miRs), particularly those shuttled via tumor‑derived exosomes, in orchestrating the complex molecular mechanisms underlying TNBC metastasis to the brain, bone, liver and lungs. In addition, the review highlights how specific miRNAs function as master regulators of organotropic metastasis by facilitating pre‑metastatic niche (PMN) formation through miRNA‑target gene‑microenvironment remodeling cascades. Key mechanisms discussed include: Brain metastasis, in which miR‑105 disrupts the blood‑brain barrier by targeting zonula occludens protein 1 and miR‑19a activates astrocytic STAT3 signaling to promote tumor extravasation and survival; bone metastasis, in which miR‑218‑5p disrupts the osteoprotegerin/receptor activator of nuclear factor κB ligand balance and miR‑21 drives a self‑perpetuating osteolysis‑growth factor‑tumor proliferation loop via programmed cell death 4/nuclear factor of activated T cells 1 and TGF‑β feedback; liver metastasis, in which miR‑122 reprograms the host metabolism by suppressing pyruvate kinase M2 and O‑GlcNAc transferase, and contributes to immune evasion; and lung metastasis, in which miR‑200 family members regulate endothelial permeability and epithelial‑mesenchymal transition. Common metastasis drivers, including miR‑10b, miR‑21, the miR‑200 family and the miR‑221/222 cluster, exhibit both shared and organ‑specific functions. Although targeting these miRNA networks holds therapeutic promise, notable challenges persist, including organ‑specific delivery efficiency, particularly across the blood‑brain barrier, potential toxicity, including miR‑10b hepatotoxicity, and scalable exosome engineering for drug delivery. Emerging strategies offering potential solutions include engineered exosomes and localized implantable systems. Understanding the spatiotemporal dynamics of miRNA‑mediated organotropism, facilitated by advanced technologies, will be crucial for the future development of precision therapies to combat TNBC metastasis.
View Figures

Figure 1

Schematic diagram of exosomal
miRNA-mediated organ-specific metastasis in TNBC. The diagram
summarizes the key mechanisms by which primary TNBC tumor-derived
exosomes deliver specific miRNAs to distinct target organs, namely
the brain, bone, liver and lungs, to remodel the microenvironment
and facilitate metastasis. In the brain, exosomes deliver miR-105
to endothelial cells, where miR-105 targets ZO-1 to disrupt the
blood-brain barrier. miR-19a is delivered to astrocytes, targeting
PTEN and SOCS1 to activate STAT3 signaling. In bone, exosomal
miR-21 targets osteoclast precursors, inhibiting PDCD4 to activate
NFATc1. miR-218-5p targets osteoblasts, inhibiting RUNX2 and OPG.
In the liver, exosomal miR-122 targets hepatocytes by inhibiting
PKM2, and skeletal muscle cells by inhibiting OGT. Exosomal miR-21
targets liver Kupffer cells, where it inhibits NF-κB signaling. In
the lungs, exosomal miR-105 targets endothelial cells by
downregulating ZO-1. miR-21 and miR-10b target pulmonary
fibroblasts, promoting their activation into cancer-associated
fibroblasts. TNBC, triple-negative breast cancer; miRNA/miR,
microRNA; ZO-1, zonula occludens protein 1; SOCS1, suppressor of
cytokine signaling 1; PDCD4, programmed cell death 4; NFATc1,
nuclear factor of activated T cells 1; RUNX2, RUNX family
transcription factor 2; OPG, osteoprotegerin; PKM2, pyruvate kinase
M2; OGT, O-GlcNAc transferase; RANKL, receptor activator of nuclear
factor κB ligand.
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Copy and paste a formatted citation
Spandidos Publications style
Bu R and Bo L: Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review). Oncol Lett 31: 151, 2026.
APA
Bu, R., & Bo, L. (2026). Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review). Oncology Letters, 31, 151. https://doi.org/10.3892/ol.2026.15504
MLA
Bu, R., Bo, L."Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)". Oncology Letters 31.5 (2026): 151.
Chicago
Bu, R., Bo, L."Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)". Oncology Letters 31, no. 5 (2026): 151. https://doi.org/10.3892/ol.2026.15504
Copy and paste a formatted citation
x
Spandidos Publications style
Bu R and Bo L: Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review). Oncol Lett 31: 151, 2026.
APA
Bu, R., & Bo, L. (2026). Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review). Oncology Letters, 31, 151. https://doi.org/10.3892/ol.2026.15504
MLA
Bu, R., Bo, L."Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)". Oncology Letters 31.5 (2026): 151.
Chicago
Bu, R., Bo, L."Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)". Oncology Letters 31, no. 5 (2026): 151. https://doi.org/10.3892/ol.2026.15504
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