LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
Copyright policy )LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
Abstract Background Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. Methods We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined an LGR5 knockdown ER− cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER− patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). Results LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER+ patients with LGR5high tumors rarely had recurrence, while high-grade ER− patients with LGR5high expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER− tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER− /triple-negative BC mouse models. Importantly, by utilizing LGR5high patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER− BC. Conclusion LGR5 has distinct roles in ER− vs. ER+ BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER− BC.
- Lund University Sweden
- Utrecht University Netherlands
- University of California, San Francisco United States
- University of Gothenburg Sweden
- Radboud University Nijmegen Medical Centre Netherlands
1117 Public Health and Health Services (for), Epidemiology, Noninfiltrating, Receptors, G-Protein-Coupled, Mice, ErbB-2, Breast cancer, 80 and over, Animals (mesh), RNA, Neoplasm, 32 Biomedical and Clinical Sciences (for-2020), RC254-282, Cancer, Aged, 80 and over, Tumor, Mice (mesh), 1112 Oncology and Carcinogenesis (for), Prognosis, Breast Cancer (rcdc), Oncology, Radiation Oncology - Radboud University Medical Center, Public Health and Health Services, Immunology, 610, Biomarkers, Tumor/analysis, G-Protein-Coupled, Noninfiltrating (mesh), 616, Middle Aged (mesh), Genetics, 3211 Oncology and carcinogenesis (for-2020), Humans, 3204 Immunology (for-2020), Tissue Array Analysis/methods, Aged, Prevention, Cancer (hrcs-hc), Prognosis (mesh), Real-Time Polymerase Chain Reaction (mesh), Carcinoma, Intraductal, Noninfiltrating/chemistry, 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Tissue Array Analysis, 4202 Epidemiology (for-2020), Adult (mesh), Receptor, ErbB-2/analysis, Biomarkers, Prevention (rcdc), Cancer Research, Women's Health (rcdc), Receptor, ErbB-2, Heterografts (mesh), Targeted therapy, Tissue Array Analysis (mesh), Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences, Receptors, 80 and over (mesh), Estrogen receptor, Cancer (rcdc), Humans (mesh), RNA, Neoplasm/isolation & purification, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, ErbB-2 (mesh), Heterografts, Female, erbB-2 (mesh), Tumor (mesh), Neoplasm (mesh), Biotechnology, Receptor, Research Article, Adult, DCIS, Oncology and Carcinogenesis, Intraductal, Breast Neoplasms, Biotechnology (rcdc), Receptors, G-Protein-Coupled/analysis, Real-Time Polymerase Chain Reaction, Cell Line, LGR5, Breast Neoplasms (mesh), Cell Line, Tumor, Breast Cancer, Journal Article, Biomarkers, Tumor, Animals, Oncology & Carcinogenesis, Biomedical and Clinical Sciences, Aged (mesh), Carcinoma, Stem Cell Research, Stem Cell Research (rcdc), Breast Neoplasms/chemistry, Carcinoma, Intraductal, Noninfiltrating, Female (mesh), Women's Health, Neoplasm, RNA, G-Protein-Coupled (mesh)
1117 Public Health and Health Services (for), Epidemiology, Noninfiltrating, Receptors, G-Protein-Coupled, Mice, ErbB-2, Breast cancer, 80 and over, Animals (mesh), RNA, Neoplasm, 32 Biomedical and Clinical Sciences (for-2020), RC254-282, Cancer, Aged, 80 and over, Tumor, Mice (mesh), 1112 Oncology and Carcinogenesis (for), Prognosis, Breast Cancer (rcdc), Oncology, Radiation Oncology - Radboud University Medical Center, Public Health and Health Services, Immunology, 610, Biomarkers, Tumor/analysis, G-Protein-Coupled, Noninfiltrating (mesh), 616, Middle Aged (mesh), Genetics, 3211 Oncology and carcinogenesis (for-2020), Humans, 3204 Immunology (for-2020), Tissue Array Analysis/methods, Aged, Prevention, Cancer (hrcs-hc), Prognosis (mesh), Real-Time Polymerase Chain Reaction (mesh), Carcinoma, Intraductal, Noninfiltrating/chemistry, 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Tissue Array Analysis, 4202 Epidemiology (for-2020), Adult (mesh), Receptor, ErbB-2/analysis, Biomarkers, Prevention (rcdc), Cancer Research, Women's Health (rcdc), Receptor, ErbB-2, Heterografts (mesh), Targeted therapy, Tissue Array Analysis (mesh), Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences, Receptors, 80 and over (mesh), Estrogen receptor, Cancer (rcdc), Humans (mesh), RNA, Neoplasm/isolation & purification, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, ErbB-2 (mesh), Heterografts, Female, erbB-2 (mesh), Tumor (mesh), Neoplasm (mesh), Biotechnology, Receptor, Research Article, Adult, DCIS, Oncology and Carcinogenesis, Intraductal, Breast Neoplasms, Biotechnology (rcdc), Receptors, G-Protein-Coupled/analysis, Real-Time Polymerase Chain Reaction, Cell Line, LGR5, Breast Neoplasms (mesh), Cell Line, Tumor, Breast Cancer, Journal Article, Biomarkers, Tumor, Animals, Oncology & Carcinogenesis, Biomedical and Clinical Sciences, Aged (mesh), Carcinoma, Stem Cell Research, Stem Cell Research (rcdc), Breast Neoplasms/chemistry, Carcinoma, Intraductal, Noninfiltrating, Female (mesh), Women's Health, Neoplasm, RNA, G-Protein-Coupled (mesh)
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