Abstract
BackgroundNovel 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.MethodsWe 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).ResultsLGR5 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.ConclusionLGR5 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.
Highlights
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
Clinical importance of leucine-rich repeat containing Gprotein-coupled receptor 5 (LGR5) in breast cancer (BC) and its prognostic value To decipher the role of LGR5 in BC we stained a BC tissue microarray (TMA) (Fig. 1a)
Further investigation of BC patients included in the METABRIC database was in line with our data showing that LGR5 gene expression was significantly higher in Estrogen receptor (ER)− BC and basal subtypes (Fig. 1b-c)
Summary
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. 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. Two patient groups subjected to overtreatment are those with ductal carcinoma in situ (DCIS) and those with estrogen receptor-positive (ER+) breast cancer (BC) [3, 4]. Similar to patients with DCIS tumors, approximately 50% of patients with low-grade ER+ tumors might end up receiving therapy without deriving clinical benefit [20]. To optimize patient care, there is a need to uncover novel diagnostic and prognostic biomarkers to discern between tumors that never become invasive and/or life threatening from those that should be targeted for treatment
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