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

Hagerling, Catharina LU ; Owyong, Mark ; Sitarama, Vaishnavi ; Wang, Chih Yang ; Lin, Charlene ; van den Bijgaart, Renske J.E. ; Koopman, Charlotte D. ; Brenot, Audrey ; Nanjaraj, Ankitha and Wärnberg, Fredrik , et al. (2020) In BMC Cancer 20(1).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, DCIS, Estrogen receptor, LGR5, Targeted therapy
in
BMC Cancer
volume
20
issue
1
article number
542
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85086355904
  • pmid:32522170
ISSN
1471-2407
DOI
10.1186/s12885-020-06986-z
language
English
LU publication?
yes
id
577a35ba-db65-497c-b873-0bbfedf71fa5
date added to LUP
2020-07-03 08:04:59
date last changed
2024-01-29 02:54:43
@article{577a35ba-db65-497c-b873-0bbfedf71fa5,
  abstract     = {{<p>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.</p>}},
  author       = {{Hagerling, Catharina and Owyong, Mark and Sitarama, Vaishnavi and Wang, Chih Yang and Lin, Charlene and van den Bijgaart, Renske J.E. and Koopman, Charlotte D. and Brenot, Audrey and Nanjaraj, Ankitha and Wärnberg, Fredrik and Jirström, Karin and Klein, Ophir D. and Werb, Zena and Plaks, Vicki}},
  issn         = {{1471-2407}},
  keywords     = {{Breast cancer; DCIS; Estrogen receptor; LGR5; Targeted therapy}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Cancer}},
  title        = {{LGR5 in breast cancer and ductal carcinoma in situ : a diagnostic and prognostic biomarker and a therapeutic target}},
  url          = {{http://dx.doi.org/10.1186/s12885-020-06986-z}},
  doi          = {{10.1186/s12885-020-06986-z}},
  volume       = {{20}},
  year         = {{2020}},
}