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Thromb Haemost 2022; 122(08): 1288-1295
DOI: 10.1055/a-1707-2130
Coagulation and Fibrinolysis

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

Marianne S. Andresen
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
,
Marit Sletten
3   Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
,
Per Morten Sandset 
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
4   Department of Haematology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
,
Nina Iversen
3   Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
,
Benedicte Stavik   *
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
,
Mari Tinholt   *
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
3   Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
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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 messenger RNA and FV protein in ERα-positive MCF-7 cells. Pretreatment 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.

Keywords

estrogen - coagulation factor V (F5) - MCF-7 cells - ER-positive breast tumors - relapse-free survival

Author Contributions

M.S.A. performed experiments, analyzed the data, and wrote the manuscript. M.S. performed experiments and critically revised the manuscript. P.M.S. critically revised the manuscript and provided funding for the study. N.I. conceived the study, performed the bioinformatics on the ERE binding sites and patient material, and critically revised the manuscript. B.S. and M.T. conceived and designed the study, performed experiments, and critically revised the manuscript.


Data Availability

The data generated during the current study are not publicly available but are available from the corresponding author on reasonable request.


* Equal contribution.


Supplementary Material



Publication History

Received: 16 April 2021

Accepted: 25 November 2021

Accepted Manuscript online:
26 November 2021

Article published online:
20 January 2022

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