ArticleBreast cancer research : BCR2023
Targeting CXCR4 abrogates resistance to trastuzumab by blocking cell cycle progression and synergizes with docetaxel in breast cancer treatment.
Article in Breast cancer research : BCR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- Special Issue "Molecular Research and Cellular Biology of Breast Cancer".International journal of molecular sciences · 2026Article
- G-CSF promotes H3K27ac-modified KLF5 to activate CXCR4 expression and drive colon cancer growth and metastasis.European journal of medical research · 2026Article
- Research Advances in Drug Resistance Mechanisms to Anti-HER2 Therapy in HER2-Positive Breast Cancer.Oncology research · 2026Review
- The role of genetics and epigenetics in breast cancer: A comprehensive review of metastasis, risk factors, and future perspectives.Journal of pharmaceutical analysis · 2025Review
- A dual-targeting peptide-drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer.Acta pharmaceutica Sinica. B · 2025Article
- Targeting the CXCR4/CXCL12 Axis to Overcome Drug Resistance in Triple-Negative Breast Cancer.Cells · 2025Review
- CXCR4 and CXCR6 dually limit T cell entry into the polyomavirus-infected brain.Journal of neuroinflammation · 2025Article
- CXCR4/CXCL12 blockade therapy; a new horizon in TNBC therapy.Medical oncology (Northwood, London, England) · 2025Review
- ComparingCancers · 2025Article
- Gallic acid potentiates the anticancer efficacy of cisplatin in ovarian cancer cells through modulation of the PI3K/AKT/mTOR and CXCL12/CXCR4 signaling pathways.Frontiers in oncology · 2025Article
- Clinical application of PBMCs in breast cancer: detection, treatment evaluation and prognosis.Frontiers in cell and developmental biology · 2025Review
- Exploring the landscape of autoimmune disorder-associated genes and their impact on immune microenvironment in breast cancer patients.American journal of translational research · 2025Article
- Proliferating CLL cells express high levels of CXCR4 and CD5.HemaSphere · 2024Article
- Article
- Resistance to FOXM1 inhibitors in breast cancer is accompanied by impeding ferroptosis and apoptotic cell death.Breast cancer research and treatment · 2024Article
- Article
- Association of the SNPs in CCL2 and CXCL12 genes with the susceptibility to breast cancer: a case-control study in China.Frontiers in oncology · 2024Article
- Tumorigenic effects of human mesenchymal stromal cells and fibroblasts on bladder cancer cells.Frontiers in oncology · 2023Article
- Cancer Stem Cells Decide the Fate of Cancer Immunotherapy by Remodeling Tumor Microenvironment.Cancer control : journal of the Moffitt Cancer CenterReview
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAlthough trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.
methodsImmunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic CXCR4 expression. Three-dimensional co-culture (tumor cells/breast cancer-associated fibroblasts/human peripheral blood mononuclear cells) or antibody-dependent cellular cytotoxicity assay was used to mimic human tumor microenvironment, which is necessary for testing therapeutic effects of CXCR4 inhibitor or trastuzumab. The FDA-approved CXCR4 antagonist AMD3100, trastuzumab, and docetaxel chemotherapy were used to evaluate therapeutic efficacy in vitro and in vivo. Reverse phase protein array and immunoblotting were used to discern the associated molecular mechanisms.
resultsUsing a panel of cell lines and patient breast cancer samples, we confirmed CXCR4 drives trastuzumab resistance in HER2+ breast cancer and further demonstrated the increased CXCR4 expression in trastuzumab-resistant cells is associated with cell cycle progression with a peak in the G2/M phases. Blocking CXCR4 with AMD3100 inhibits cell proliferation by downregulating mediators of G2-M transition, leading to G2/M arrest and abnormal mitosis. Using a panel of trastuzumab-resistant cell lines and an in vivo established trastuzumab-resistant xenograft mouse model, we demonstrated that targeting CXCR4 with AMD3100 suppresses tumor growth in vitro and in vivo, and synergizes with docetaxel.
conclusionsOur findings support CXCR4 as a novel therapeutic target and a predictive biomarker for trastuzumab resistance in HER2+ breast cancer.
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