Protein C receptor is a therapeutic stem cell target in a distinct group of breast cancers


Breast cancer is a heterogeneous disease. In particular, triple-negative breast cancer (TNBC) comprises various molecular subgroups with unclear identities and currently has few targeted treatment options. Our previous study identified protein C receptor (Procr) as a surface marker on mammary stem cells (MaSCs) located in the basal layer of the normal mammary gland. Given the possible connection of TNBC with basal layer stem cells, we conducted comparative analyses of Procr in breast cancers of mouse and human origin. In mouse mammary tumors, we showed that Procr+ cells are enriched for cancer stem cells (CSCs) in Wnt1 basal-like tumors, but not in Brca1 basal-like tumors or PyVT luminal tumors. In human cancers, PROCR was robustly expressed in half of TNBC cases. Experiments with patient-derived xenografts (PDXs) revealed that PROCR marks CSCs in this discrete subgroup (referred to as PROCR+ TNBC). Interfering with the function of PROCR using an inhibitory nanobody reduced the CSC numbers, arrested tumor growth and prevented rapid tumor recurrence. Our data suggest a key role of MaSC in breast tumorigenesis. Moreover, our work indicates that PROCR can be used as a biomarker to stratify TNBC into clinically relevant subgroups and may provide a novel targeted treatment strategy for this clinically important tumor subtype.

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We are grateful to Drs. Chi-Chung Hui, Esther Verheyen and Roel Nusse for critical reading of the manuscript. We thank Drs. Dangsheng Li and Weiguo Zou for helpful discussion. We thank Dr. Suling Liu for providing reagents. We thank Dr. Jianhua Sui for advice on antibody development. This work was supported by grants from National Natural Science Foundation of China (31830056, 31861163006, 31625020, 31530045, 31661143043 to Y.A.Z, 81874113 to Z.-M.S; 81672601, 81872137 to X.H.), Chinese Academy of Sciences (XDA12020378 to Y.J. and XDB19000000 to Y.A.Z.), Shanghai Municipal Science and Technology Commission (17XD1404000 to Y.A.Z.) and National Ten Thousand Talents Program (to Y. A. Z.).

Author information

Y.A.Z and Z.-M.S conceived the study. D.W. performed most FACS analyses, genetic, xenograft and in vitro experiments. C.L., R.Y. performed xenograft, antibody and chemo agent administration. D.W., Y.J., C.C. and L.B. performed monoclonal antibody screening and characterization. J.W. performed mouse breeding. X.H., S.L., F.Q., L.Y., L.C. and Z.-M.S provided TMA and PDX samples. Y.B. and Y.-R.L performed bioinformatics analysis. D.W., X.H. and Y.A.Z. analyzed the data and wrote the manuscript. C.L., G.G., H.J., D.L., L.L. and J.C. helped project design and manuscript editing.

Correspondence to Zhi-Ming Shao or Yi Arial Zeng.

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The authors declare no competing interests.

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