Abstract
Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, to be positively correlated with relapse-free, metastasis-free, or overall survival in breast cancer. In addition, CD177 expression is correlated with good prognosis in several other solid cancers including prostate, cervical, and lung. Focusing on breast cancer, we found that CD177 is expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis. Mechanistically, we found that CD177-deficiency is associated with an increase in β-catenin signaling. Here we identified CD177 as a novel regulator of mammary epithelial proliferation and breast cancer pathogenesis likely via the modulation of Wnt/β-catenin signaling pathway, a key signaling pathway involved in multiple cancer types.
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Acknowledgements
W.Z. was supported by NIH grants CA200673 and CA203834, the V Scholar award, American Cancer Society seed grant, Breast Cancer Research Award and Oberley Award (National Cancer Institute Award P30CA086862) from Holden Comprehensive Cancer Center at the University of Iowa, University of Iowa. N.B. was supported by NIH CA206255. Q.X. was supported by the National Natural Science Foundation of China (No. 81502313). We thank Dr. Foekens for sharing the site-specific metastasis information related to GSE2034. We thank Dr. Shay for sharing the human colon epithelial cells.
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P.N.K., R.K., D.Z., X.S., and W.Z. conceived and designed the experiments. R.K. and Q.X. obtained the mouse tumor data. R.K., P.N.K., Q.X., Q.L.L., M.K., Y.L. did the biochemical studies. P.N.K., Y.L. performed the immunofluorescent staining, immunohistochemistry, and analysis of normal mammary gland. N.B. processed the RNAseq data and obtained methylation data. W.L., C.S., L.W., and A.W.T. provided technical support. A.B. provided TMAs and assigned IHC scores. K.N.G. and C.Z. provided histological help on tumor and tumor mammary tissues., S.S. and R.J.W. provided human breast cancer protein, RNA and tissue samples. R.K., P.N.K., X.S., D.Z., and W.Z. analyzed the data and wrote the manuscript. W.Z. supervised the whole project.
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Kluz, P.N., Kolb, R., Xie, Q. et al. Cancer cell-intrinsic function of CD177 in attenuating β-catenin signaling. Oncogene 39, 2877–2889 (2020). https://doi.org/10.1038/s41388-020-1203-x
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DOI: https://doi.org/10.1038/s41388-020-1203-x
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