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

Abstract

Most breast cancers express estrogen receptor (ER) where estrogen signaling plays an important role. Cancer contributes to activation of the coagulation system leading to an imbalance in the hemostatic system, and Coagulation factor (F) V, which is a key regulator of blood coagulation, has been shown to be increased in breast tumors. Thus, the molecular association between estrogens and FV was explored. Stimulation with 17-β-estradiol (E2) or 17-β-ethinylestradiol (EE2) resulted in a time- and dose-dependent increase in F5 mRNA and FV protein in ERα positive MCF-7 cells. Pre-treatment with the ER antagonist fulvestrant or knockdown of ERα prior to stimulation with E2 counteracted this effect. Three ERα binding half-sites were identified in the promoter region of the F5 gene in silico. Reporter gene analysis showed that all three half-sites were involved in the estrogen-induced gene regulation in vitro, as the effect was abolished only when all half-sites were mutated. High F5 levels in ER positive breast tumors were associated with increased relapse-free survival of breast cancer patients.

Genetic variants in African‑American and Hispanic patients with breast cancer

“…Among genes that showed a higher frequency in our cohort were F5 and MTHFR , with possible germline contributions. However, F5 is a potential candidate gene for breast cancer and a marker for immune cell infiltration in breast cancer ( 30 , 31 ). PRSS1, SETD8 , and CDC27 were frequently mutated in African-American and Hispanic samples.…”

“…In colon and breast cancers, 5-Fluorouracila sensitivity is associated with variants in the MTHFR gene ( 36 , 37 ). F5 (Coagulation factor V) is an estrogen response gene associated with CD8+ T cell in cancer immunity ( 30 , 38 ). These genes are also associated with the TGF-β pathway.…”