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Breast Cancer Research and Treatment

, Volume 148, Issue 1, pp 41–59 | Cite as

Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome

  • Katherine Drews-ElgerEmail author
  • Elizabeth Iorns
  • Alexandra Dias
  • Philip Miller
  • Toby M. Ward
  • Sonja Dean
  • Jennifer Clarke
  • Adriana Campion-Flora
  • Daniel Nava Rodrigues
  • Jorge S. Reis-Filho
  • James M. Rae
  • Dafydd Thomas
  • Deborah Berry
  • Dorraya El-Ashry
  • Marc E. Lippman
Preclinical Study

Abstract

The mechanisms by which breast cancer (BrC) can successfully metastasize are complex and not yet fully understood. Our goal was to identify tumor-induced stromal changes that influence metastatic cell behavior, and may serve as better targets for therapy. To identify stromal changes in cancer-bearing tissue, dual-species gene expression analysis was performed for three different metastatic BrC xenograft models. Results were confirmed by immunohistochemistry, flow cytometry, and protein knockdown. These results were validated in human clinical samples at the mRNA and protein level by retrospective analysis of cohorts of human BrC specimens. In pre-clinical models of BrC, systemic recruitment of S100A8+ myeloid cells—including myeloid-derived suppressor cells (MDSCs)—was promoted by tumor-derived factors. Recruitment of S100A8+ myeloid cells was diminished by inhibition of tumor-derived factors or depletion of MDSCs, resulting in fewer metastases and smaller primary tumors. Importantly, these MDSCs retain their ability to suppress T cell proliferation upon co-culture. Secretion of macrophage inhibitory factor (MIF) activated the recruitment of S100A8+ myeloid cells systemically. Inhibition of MIF, or depletion of MDSCs resulted in delayed tumor growth and lower metastatic burden. In human BrC specimens, increased mRNA and protein levels of S100A8+ infiltrating cells are highly associated with poor overall survival and shorter metastasis free survival of BrC patients, respectively. Furthermore, analysis of nine different human gene expression datasets confirms the association of increased levels of S100A8 transcripts with an increased risk of death. Recruitment of S100A8+ myeloid cells to primary tumors and secondary sites in xenograft models of BrC enhances cancer progression independent of their suppressive activity on T cells. In clinical samples, infiltrating S100A8+ cells are associated with poor overall survival. Targeting these molecules or associated pathways in cells of the tumor microenvironment may translate into novel therapeutic interventions and benefit patient outcome.

Keywords

S100A8 Myeloid-derived suppressor cells (MDSCs) Inflammation and tumor development Cytokines Molecular markers of metastasis and progression 

Notes

Acknowledgments

The authors would like to thank the members of the Oncogenomics Core Facility, Flow Cytometry Core Facility, and the Division of Veterinary Resources at the University of Miami Miller School of Medicine for their assistance during the course of the study. The authors would also like to thank Nanette Bishopric, MD and Barry I. Hudson PhD for helpful discussion of the manuscript. This Project was funded by Breast Cancer Research Foundation (BrCRF) awards to MEL and JMR. Part of these studies was conducted at the Lombardi Comprehensive Cancer Center Histopathology and Tissue Shared Resource which is supported in part by NIH/NCI Grant P30-CA051008. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Conflict of interest

All authors have no conflicts of interest to declare.

Supplementary material

10549_2014_3122_MOESM1_ESM.pdf (733 kb)
Supplementary material 1 (PDF 733 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Katherine Drews-Elger
    • 1
    Email author
  • Elizabeth Iorns
    • 2
  • Alexandra Dias
    • 1
  • Philip Miller
    • 1
  • Toby M. Ward
    • 3
  • Sonja Dean
    • 1
  • Jennifer Clarke
    • 1
  • Adriana Campion-Flora
    • 4
  • Daniel Nava Rodrigues
    • 4
  • Jorge S. Reis-Filho
    • 5
  • James M. Rae
    • 6
  • Dafydd Thomas
    • 7
  • Deborah Berry
    • 8
  • Dorraya El-Ashry
    • 1
  • Marc E. Lippman
    • 1
  1. 1.Department of MedicineUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Science ExchangePalo AltoUSA
  3. 3.Stanford Cancer InstituteStanford University School of MedicineStanfordUSA
  4. 4.Breakthrough Breast Cancer Research CenterThe Institute of Cancer ResearchLondonUK
  5. 5.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Breast Oncology Program, 6312 CCGCUniversity of Michigan Medical SchoolAnn ArborUSA
  7. 7.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  8. 8.Histopathology & Tissue Shared Resource, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA

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