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.

Construction of Potential Gene Expression and Regulation Networks in Prostate Cancer Using Bioinformatics Tools

“…Garber et al found that F5 gene variation was associated with breast cancer. The F5 expression was enriched in breast cancer and was associated with overall survival [27]; moreover, the F5 gene was associated with the risk of thrombosis in cancer patients [28]. F5 is also associated with the risk of thrombosis in patients with metastatic androgen-dependent prostate cancer who undergo diethylstilbestrol and docetaxel chemotherapy [29].…”

Polypeptide-GalNAc-Transferase-13 Shows Prognostic Impact in Breast Cancer

“…Tumors with high expression of F5 exhibit an increased inflammatory infiltration, with lymphoid and myeloid cells. This is probably related to a better immune anti-tumor response, which could explain the better prognostic of such tumors, suggesting a potential opportunity for novel therapeutic strategies [ 57 ]. Frizzled 6 belongs to a family of transmembrane receptors for Wnt signaling proteins, frequently amplified in breast cancer, mainly in triple-negative molecular type [ 58 ].…”

Coagulation Factor V (F5) is an Estrogen-Responsive Gene in Breast Cancer Cells

“…We have previously shown that FV levels are increased in breast cancer tissue compared to normal breast tissue and that the F5 mRNA levels are higher in ER negative breast tumors, suggesting a role of FV in breast cancer. Moreover, high levels of F5 mRNA in breast tumors are associated with a better overall breast cancer survival 8 and relapse-free survival 7 . Studies on the molecular mechanisms regulating FV levels in breast cancer are lacking, however, estrogen-containing hormone treatment has been shown to increase F5 mRNA levels in post-menopausal women previously 18 .…”

“…We have previously reported that breast cancer patients with basal tumors (which are triple negative of the hormone receptors) expressing higher levels of F5 had better overall survival rates compared to patients with lower F5 tumor expression 8 . Moreover, high F5 in tumors from breast cancer patients has been shown to be associated with an improved relapse-free survival, independent of breast cancer subtype 7 . Here we also report that relapse-free survival in patients with ER positive breast cancer expressing higher levels of F5 are associated with increased survival.…”

“…The reason for these opposite findings is not known, however, estrogen and other unknown microenvironmental factors like different amount of immune infiltration in the tumors may affect the behavior of F5 differently in various cancers. The difference in the functional annotation analyses from the F5 co-expressed genes in breast 7 (immune responsive genes) and gastric cancer 36 (glycerophospholipid metabolism) support this assumption. Our study also confirms that the increase in gene expression was mediated to the protein level as intracellular FV protein was increased following estrogen stimulation.…”