ArticleEMBO molecular medicine2021
uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.
Article in EMBO molecular medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- Obesity-driven adipokine signaling in breast cancer: mechanistic insights, therapeutic challenges, and opportunities for precision oncology.Journal of pathology and translational medicine · 2026Article
- Plasmin promotes hepatocellular carcinoma invasion and metastasis via CXCR4-mediated activation of PI3K/AKT/mTOR signaling.Oncogene · 2026Article
- Emerging roles of haemostatic proteins as markers of disease progression and prognosis in breast cancer.Exploration of targeted anti-tumor therapy · 2026Review
- Therapeutic efficacy of budesonide suspension combined with poractant alfa injection for neonatal respiratory distress syndrome and its effect on serum ferritin and PAI-1 expressions.Pakistan journal of medical sciences · 2025Article
- SEPT9 and PAI-1 are immunohistochemical biomarkers of the hepatocellular carcinoma immune microenvironment.Discover oncology · 2025Article
- HER-2-Targeted Electrochemical Sensors for Breast Cancer Diagnosis: Basic Principles, Recent Advancements, and Challenges.Biosensors · 2025Review
- Adipokines in Breast Cancer: Decoding Genetic and Proteomic Mechanisms Underlying Migration, Invasion, and Proliferation.Breast cancer (Dove Medical Press) · 2025Article
- A cross-sectional study on the expression of fibrinolytic system components and metalloproteinase-9 in women with early-stage and metastases breast cancer in Tucumán, Argentina.Einstein (Sao Paulo, Brazil) · 2025Article
- Review
- Progress in Research on Key Factors Regulating Lactation Initiation in the Mammary Glands of Dairy Cows.Genes · 2023Review
- Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19.Frontiers in immunology · 2023Article
- Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.Science advances · 2022Article
- uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.EMBO molecular medicine · 2021Article
Corrections and comments
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Authors and funding
23 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
High intratumoral levels of urokinase-type plasminogen activator (uPA)-plasminogen activator inhibitor-1 (PAI-1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI-1 multiplies the potential of the single proteins to attract pro-tumorigenic neutrophils. To this end, tumor-released uPA-PAI-1 utilizes very low-density lipoprotein receptor and mitogen-activated protein kinases to initiate a pro-inflammatory program in perivascular macrophages. This enforces neutrophil trafficking to cancerous lesions and skews these immune cells toward a pro-tumorigenic phenotype, thus supporting tumor growth and metastasis. Blockade of uPA-PAI-1 heteromerization by a novel small-molecule inhibitor interfered with these events and effectively prevented tumor progression. Our findings identify a therapeutically targetable, hitherto unknown interplay between hemostasis and innate immunity that drives breast cancer progression. As a personalized immunotherapeutic strategy, blockade of uPA-PAI-1 heteromerization might be particularly beneficial for patients with highly aggressive uPA-PAI-1
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