LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
Catharina Hagerling, Mark Owyong, Vaishnavi Sitarama, Chih‐Yang Wang, Charlene Lin, Renske J.E. van den Bijgaart, Charlotte D. Koopman, Audrey Brenot, Ankitha Nanjaraj, Fredrik Wärnberg, Karin Jirström, Ophir D. Klein, Zena Werb, Vicki Plaks
Abstract
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.