ArticleBreast cancer research : BCR2025
Cancer-associated fibroblast driven paracrine IL-6/STAT3 signaling promotes migration and dissemination in invasive lobular carcinoma.
Article in Breast cancer research : BCR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Toward targeted therapeutics for lobular breast cancer.The Journal of clinical investigation · 2026Review
- Transcriptomic Insights into Lobular Breast Cancer Biology and Patient Outcomes: Analysis of the MINDACT Clinical Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Treg-derived exosomal miR-146a orchestrates bidirectional Treg-CAF crosstalk to sustain immunosuppressive tumor microenvironments.Medical oncology (Northwood, London, England) · 2026Review
- Cytokines and cancer-associated fibroblasts.Journal of hematology & oncology · 2026Review
- Serum amyloid A1 promote progression of breast cancer and is associated with epithelial-mesenchymal transition.Translational cancer research · 2026Article
- The metabolic profiles of cancer stem cells.Stem cell research & therapy · 2026Review
- High Expression of PAPP-A Predicts Poor Outcomes in Oestrogen Receptor-Positive Breast Cancer Patients.Cancer medicine · 2026Article
- IL‑6: A key player in the EGFR‑TKI‑resistant tumor microenvironment and its therapeutic implications (Review).International journal of oncology · 2026Review
- Preclinical models of breast cancer metastasis: strengths, limitations, and clinical relevance.NPJ breast cancer · 2026Review
- Out of Nucleus: Serine 727 Phosphorylation Orchestrates Non-Canonical STAT3 Functions-Relevance to Triple-Negative Breast Cancer.International journal of molecular sciences · 2026Review
- Cancer-Associated Fibroblast-Targeted Nanomedicine in Solid Tumor Therapy: From Mechanisms of Therapeutic Resistance to Precision Stromal Modulation.International journal of nanomedicine · 2026Review
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24 authors.
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Abstract
backgroundInvasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma of no special type (NST), accounting for 10-15% of diagnoses. Despite the myriad molecular, histological and clinical differences between ILC and NST tumors, patients are treated in the same way, and although prognosis initially is good, ILC patients have poorer long-term outcomes. Understanding the differences between these two subtypes and identifying ILC-enriched therapeutic targets is necessary to improve patient care.
methodsHuman and mouse cancer-associated fibroblasts (CAFs), ILC cell lines and patient-derived organoids were used for in vitro and in vivo studies, including western blotting, migration, organotypic invasion assays and dissemination in zebrafish embryos. RNASeq was used to identify CAF and interleukin-6 (IL-6)-derived gene signatures. Bioinformatic analysis of public databases and immunohistochemical of human tumor microarrays was carried out.
resultsWe identified IL-6 as a paracrine CAF-derived factor that activates Signal-Transducer-and-Activator-of-Transcription-3 (STAT3) in human and mouse ILC models. Analysis of human breast tumors showed that the IL-6/JAK/STAT3 pathway is enriched in ER + ILC compared to ER + NST. A 42-gene CAF dependent IL-6 gene signature and 64-gene consensus IL-6 gene signature were generated and were significantly enriched in ER + ILC, with many of the genes overexpressed in ILC tumors. IL-6 treatment suppressed downstream estrogen signaling and also led to the acquisition of a more mesenchymal-like phenotype associated with increased migration and invasion. Finally, IL-6 treatment significantly increased ILC cell dissemination following injection into zebrafish embryos.
conclusionsCAF-derived IL-6 drives paracrine activation of the IL6/JAK/STAT3 signaling pathway which is enriched in ILC. This leads to the acquisition of pro-tumorigenic phenotypes, highlighting the pathway as a potential therapeutic target in ILC.
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