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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 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.

SUBMITTER: Hagerling C

PROVIDER: S-EPMC7285764 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Hagerling Catharina C Owyong Mark M Sitarama Vaishnavi V Wang Chih-Yang CY Lin Charlene C van den Bijgaart Renske J E RJE Koopman Charlotte D CD Brenot Audrey A Nanjaraj Ankitha A Wärnberg Fredrik F Jirström Karin K Klein Ophir D OD Werb Zena Z Plaks Vicki V

BMC cancer 20200610 1

<h4>Background</h4>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 tar ...[more]

PMID: 32522170

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Dataset Information

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

Publications

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

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