ArticleCancer research2023
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 96 citations in OpenAlex.
- TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.Breast cancer research : BCR · 2024Trial
- Histone H4 lysine 20 tri-methylation safeguards breast cancer lineage fidelity and unfolded protein response.Nature communications · 2026Article
- Flavonoid-modulated JAK-STAT signaling mitigates malignant transformation and drug resistance in breast tumors: A clinically relevant 3PM-guided innovation.Journal of advanced research · 2026Review
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Beyond suppression: the paradox of JAK inhibitors as amplifiers of cancer immunotherapy.Nature reviews. Immunology · 2026Review
- A Novel Patient-Derived Xenograft Model of Inflammatory Breast Cancer.Research square · 2026Article
- From State, Pathway, to Niche: The Ternary Network of Breast Cancer Stem-like Cells Driving Tumor Progression and Combination Therapy Prospects.Biomolecules · 2026Review
- Discovery of SD-965 as a Potent, Selective, and Efficacious STAT3 PROTAC Degrader.Journal of medicinal chemistry · 2026Article
- Therapy as a State-Generator: Dynamic Phenotypic Landscapes and Adaptive Stress Circuits in Chemotherapy Resistance of Breast Cancer.Antioxidants (Basel, Switzerland) · 2026Review
- CXCL8/SDC1 axis mediates tumor stem cell interactions to drive remote transfer in thyroid cancer.Journal of pharmaceutical analysis · 2026Article
- scDrugMap: benchmarking large foundation models for drug response prediction.Nature communications · 2025Article
- Decoding breast cancer: insights into molecular pathways & therapeutic approaches.Discover oncology · 2025Review
- Association of urinary tract infection and low albumin/globulin ratio with chemoresistance to gemcitabine-cisplatin in advanced urothelial carcinoma.The Canadian journal of urology · 2025Article
- Synthesis and Biological Evaluation of Herceptin-Conjugated Liposomes Loaded with Lipocalin-2 siRNA for the Treatment of Inflammatory Breast Cancer.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Bisphenol A Promotes the Progression of Hormone-Sensitive Breast Cancers Through Several Inflammatory Pathways.Cancers · 2025Review
- Clinicogenomic Characterization of Inflammatory Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- CyTOF as a suitable tool for stratification and monitoring of cancer patients.Journal of translational medicine · 2025Review
- Investigating the Potential Therapeutic Targeting of the JAK-STAT Pathway in Cerebrovascular Diseases: Opportunities and Challenges.Molecular neurobiology · 2025Review
- Engineering Lipid-Polymer Nanoparticles for siRNA Delivery to Cancer Cells.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Application of mass cytometry in the immune microenvironment of breast cancer.Medical oncology (Northwood, London, England) · 2025Review
Corrections and comments
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Authors and funding
33 authors at 7 institutions in 2 countries.
Funding
Abstract
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC. SIGNIFICANCE: Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.