Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development

Florence Schaffner, Naho Yokota, Tatiana Lobo, Maki Kitano, Michael Schaffer, G. Mark Anderson, Barbara M. Mueller, Charles T. Esmon, Wolfram Ruf

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Article numbere61071
JournalPLoS One
Volume8
Issue number4
DOIs
Publication statusPublished - 9 Apr 2013
Externally publishedYes

Fingerprint

Protein C
breast neoplasms
Tumors
Breast Neoplasms
Neoplastic Stem Cells
Stem cells
receptors
mice
proteins
stem cells
Neoplasms
neoplasms
Growth
Stem Cells
Triple Negative Breast Neoplasms
Population
Cells
Blocking Antibodies
Tumor Microenvironment
Cell Surface Receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Schaffner, F., Yokota, N., Lobo, T., Kitano, M., Schaffer, M., Anderson, G. M., ... Ruf, W. (2013). Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development. PLoS One, 8(4), [e61071]. https://doi.org/10.1371/journal.pone.0061071

Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development. / Schaffner, Florence; Yokota, Naho; Lobo, Tatiana; Kitano, Maki; Schaffer, Michael; Anderson, G. Mark; Mueller, Barbara M.; Esmon, Charles T.; Ruf, Wolfram.

In: PLoS One, Vol. 8, No. 4, e61071, 09.04.2013.

Research output: Contribution to journalArticle

Schaffner, F, Yokota, N, Lobo, T, Kitano, M, Schaffer, M, Anderson, GM, Mueller, BM, Esmon, CT & Ruf, W 2013, 'Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development', PLoS One, vol. 8, no. 4, e61071. https://doi.org/10.1371/journal.pone.0061071
Schaffner, Florence ; Yokota, Naho ; Lobo, Tatiana ; Kitano, Maki ; Schaffer, Michael ; Anderson, G. Mark ; Mueller, Barbara M. ; Esmon, Charles T. ; Ruf, Wolfram. / Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development. In: PLoS One. 2013 ; Vol. 8, No. 4.
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