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LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target

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Název: LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
Autoři: Hagerling, Catharina, Owyong, Mark, Sitarama, Vaishnavi, Wang, Chih-Yang, Lin, Charlene, van den Bijgaart, Renske J E, Koopman, Charlotte D, Brenot, Audrey, Nanjaraj, Ankitha, Wärnberg, Fredrik, Jirström, Karin, Klein, Ophir D, Werb, Zena, Plaks, Vicki
Přispěvatelé: Hubrecht Institute with UMC
Rok vydání: 2020
Témata: Adult, Aged, 80 and over, Animals, Biomarkers, Tumor/analysis, Breast Neoplasms/chemistry, Carcinoma, Intraductal, Noninfiltrating/chemistry, Cell Line, Tumor, Female, Heterografts, Humans, Mice, Middle Aged, Prognosis, RNA, Neoplasm/isolation & purification, Real-Time Polymerase Chain Reaction, Receptor, ErbB-2/analysis, Receptors, G-Protein-Coupled/analysis, Tissue Array Analysis/methods, Estrogen receptor, Targeted therapy, Breast cancer, DCIS
Popis: 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.
Druh dokumentu: article in journal/newspaper
Popis souboru: application/pdf
Jazyk: English
ISSN: 1471-2407
Relation: https://dspace.library.uu.nl/handle/1874/442201
Dostupnost: https://dspace.library.uu.nl/handle/1874/442201
Rights: info:eu-repo/semantics/OpenAccess
Přístupové číslo: edsbas.1243E6D1
Databáze: BASE
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  Data: LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
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  Data: <searchLink fieldCode="AR" term="%22Hagerling%2C+Catharina%22">Hagerling, Catharina</searchLink><br /><searchLink fieldCode="AR" term="%22Owyong%2C+Mark%22">Owyong, Mark</searchLink><br /><searchLink fieldCode="AR" term="%22Sitarama%2C+Vaishnavi%22">Sitarama, Vaishnavi</searchLink><br /><searchLink fieldCode="AR" term="%22Wang%2C+Chih-Yang%22">Wang, Chih-Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Lin%2C+Charlene%22">Lin, Charlene</searchLink><br /><searchLink fieldCode="AR" term="%22van+den+Bijgaart%2C+Renske+J+E%22">van den Bijgaart, Renske J E</searchLink><br /><searchLink fieldCode="AR" term="%22Koopman%2C+Charlotte+D%22">Koopman, Charlotte D</searchLink><br /><searchLink fieldCode="AR" term="%22Brenot%2C+Audrey%22">Brenot, Audrey</searchLink><br /><searchLink fieldCode="AR" term="%22Nanjaraj%2C+Ankitha%22">Nanjaraj, Ankitha</searchLink><br /><searchLink fieldCode="AR" term="%22Wärnberg%2C+Fredrik%22">Wärnberg, Fredrik</searchLink><br /><searchLink fieldCode="AR" term="%22Jirström%2C+Karin%22">Jirström, Karin</searchLink><br /><searchLink fieldCode="AR" term="%22Klein%2C+Ophir+D%22">Klein, Ophir D</searchLink><br /><searchLink fieldCode="AR" term="%22Werb%2C+Zena%22">Werb, Zena</searchLink><br /><searchLink fieldCode="AR" term="%22Plaks%2C+Vicki%22">Plaks, Vicki</searchLink>
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  Data: Hubrecht Institute with UMC
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– Name: Abstract
  Label: Description
  Group: Ab
  Data: 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.
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      – Text: English
    Subjects:
      – SubjectFull: Adult
        Type: general
      – SubjectFull: Aged
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      – SubjectFull: 80 and over
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      – SubjectFull: Breast cancer
        Type: general
      – SubjectFull: DCIS
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      – TitleFull: LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
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