title: Endothelial protein C receptor function in murine and human breast cancer development.
abstract: Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. Mice with a hypomorphic allele of EPCR show reduced tumor growth in the PyMT-model of spontaneous breast cancer development and deletion of EPCR in established PyMT tumor cells significantly attenuates transplanted tumor take and growth. We find expansion of EPCR(+) cancer stem cell-like populations in aggressive, mammary fat pad-enhanced human triple negative breast cancer cells. In this model, EPCR-expressing cells have markedly increased mammosphere- and tumor-cell initiating activity compared to another stable progenitor-like subpopulation present at comparable frequency. We show that receptor blocking antibodies to EPCR specifically attenuate in vivo tumor growth initiated by either EPCR(+) cells or the heterogenous mixture of EPCR(+) and EPCR(-) cells. Furthermore, we have identified tumor associated macrophages as a major source for recognized ligands of EPCR, suggesting a novel mechanism by which cancer stem cell-like populations are regulated by innate immune cells in the tumor microenvironment.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Florence
authors.initials: F
authors.lastname: Schaffner
authors.forename: Naho
authors.initials: N
authors.lastname: Yokota
authors.forename: Tatiana
authors.initials: T
authors.lastname: Carneiro-Lobo
authors.forename: Maki
authors.initials: M
authors.lastname: Kitano
authors.forename: Michael
authors.initials: M
authors.lastname: Schaffer
authors.forename: G Mark
authors.initials: GM
authors.lastname: Anderson
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Mueller
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; C478370:PROCR protein, human; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface