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LGR5 in breast canc...
LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
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- Hagerling, Catharina (author)
- Lund University,Lunds universitet,Cancercellers evolution,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Pathways of cancer cell evolution,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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- Owyong, M. (author)
- University of California, San Francisco,UCSF Helen Diller Family Comprehensive Cancer Center
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- Sitarama, V. (author)
- UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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- Wang, C. Y. (author)
- National Cheng Kung University,UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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- Lin, C. (author)
- University of California, San Francisco,UCSF Helen Diller Family Comprehensive Cancer Center
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- van den Bijgaart, R. J. E. (author)
- UCSF Helen Diller Family Comprehensive Cancer Center,Radboud University Medical Center,University of California, San Francisco
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- Koopman, C. D. (author)
- University of California, San Francisco,University Medical Center Utrecht,UCSF Helen Diller Family Comprehensive Cancer Center
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- Brenot, A. (author)
- Washington University in St. Louis,University of California, San Francisco,UCSF Helen Diller Family Comprehensive Cancer Center
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- Nanjaraj, A. (author)
- University of California, San Francisco,UCSF Helen Diller Family Comprehensive Cancer Center
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- Wärnberg, Fredrik (author)
- University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,Sahlgrenska University Hospital
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- Jirström, Karin (author)
- Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Klein, O. D. (author)
- University of California, San Francisco
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- Werb, Z. (author)
- UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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- Plaks, V. (author)
- UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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(creator_code:org_t)
- 2020-06-10
- 2020
- English.
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In: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Abstract
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- 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 anLGR5knockdown 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 LGR5(high)tumors rarely had recurrence, while high-grade ER(-)patients with LGR5(high)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 LGR5(high)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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- LGR5
- Breast cancer
- DCIS
- Estrogen receptor
- Targeted therapy
- mammary stem-cells
- genomic differences
- small-intestine
- self-renewal
- progression
- identification
- marker
- overdiagnosis
- overtreatment
- mammography
- Oncology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Bmc Cancer
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To the university's database
- By the author/editor
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Hagerling, Catha ...
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Owyong, M.
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Sitarama, V.
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Wang, C. Y.
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Lin, C.
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van den Bijgaart ...
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show more...
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Koopman, C. D.
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Brenot, A.
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Nanjaraj, A.
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Wärnberg, Fredri ...
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Jirström, Karin
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Klein, O. D.
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Werb, Z.
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Plaks, V.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Bmc Cancer
- By the university
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University of Gothenburg
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Lund University