Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer

ABSTRACT

Background

Factor (F) V is an essential cofactor in blood coagulation, however, F5 expression in breast tumors has also been linked to tumor aggressiveness and overall survival. The specific role of FV in breast cancer is yet unknown. We therefore aimed at dissecting the biological relevance of FV in breast cancer.

Methods

Gene expression data from a Scandinavian breast cancer cohort (n = 363) and the cancer genome atlas (TCGA) (n = 981) and 12 replication cohorts were used to search for F5 co-expressed genes, followed by gene ontology analysis. Pathological and bioinformatic tools were used to evaluate immune cell infiltration and tumor purity. T cell activation, proliferation and migration were studied in FV treated Jurkat T cells.

Results

F5 co-expressed genes were mainly associated with immune system processes and cell activation. Tumors with high expression of F5 were more infiltrated with both lymphoid (T cells, NK cells, and B cells) and myeloid cells (macrophages and dendritic cells), and F5 expression was negatively correlated with tumor purity (ρ = −0.32). Confirming a prognostic role, data from the Kaplan-Meier plotter showed that high F5 expression was associated with improved relapse-free survival. The strongest association was observed in basal-like breast cancer (HR = 0.55; 95% CI, 0.42–0.71). Exogenous FV did not substantially affect activation, proliferation or migration of human T cells.

Conclusions

F5 was identified as a novel marker of immune cell infiltration in breast cancer, and the prognostic role of F5 was verified. FV emerge as an interesting immunological biomarker with potential therapeutic relevance for the cancer-inflammation-thrombosis circuit.

KEYWORDS:

• Blood coagulation
• factor V
• breast neoplasm
• survival
• cellular Immune Response

Acknowledgments

We would like to thank Oslo Breast Cancer Consortium (OSBREAC) for providing patient samples (http://breastcancerresearch.no/osbreac/), Eldri Undlien Due for tumor preparation, and Elsa Beraki for IHC staining.

Abbreviations

F: factor; TCGA: the cancer genome atlas; ELISA; enzyme-linked immunosorbent assay; WST-1: Water Soluble Tetrazolium Salt-1; H-E staining: hematoxylin and eosin staining; HR: hazard ratio; APC: activated protein C; TF: tissue factor; PAR: protease activated receptor; GEO: Gene Expression Omnibus; FDR: false discovery rate; GO: gene ontology; PHA: phytohaemagglutinin; IL-2: interleukin-2; NK cells: natural killer cells; Treg cells: regulatory T cells

Addendum

M Tinholt designed the study, analyzed and interpreted the data, performed in vitro experiments, and wrote the paper. B Stavik substantially contributed to the in vitro experiments. X Tekpli conducted statistical analyses and interpreted the data. E Borgen and Ø Garred performed the pathological evaluation of tumors. V Kristensen, K.K. Sahlberg, and N Iversen participated in the acquisition of the data. P.M. Sandset and N Iversen conceived the project. N Iversen designed and supervised the project. B Stavik, X Tekpli, E Borgen, Ø Garred, V Kristensen, K.K. Sahlberg, P.M. Sandset, and N Iversen critically revised the intellectual content of the paper. All authors read and approved the final manuscript.

Disclosure of interest

The authors declare that they have no competing interests.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work was supported by the South-Eastern Norway Regional Health Authority (Hamar, Norway) under grant no. 2017098.