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

Marianne S. Andresen; Marit Sletten; Per Morten Sandset; Nina Iversen; Benedicte Stavik; Mari Tinholt

doi:10.1055/a-1707-2130

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

,

Marit Sletten

³Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

,

Per Morten Sandset

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

⁴Department of Haematology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

,

Nina Iversen

³Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

,

Benedicte Stavik^*

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

,

Mari Tinholt^*

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

³Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

› Author Affiliations

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

Full Text

References

References
1 Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11 (02) 223-233
2 Leiva O, Newcomb R, Connors JM, Al-Samkari H. Cancer and thrombosis: new insights to an old problem. J Med Vasc 2020; 45 (6S): S8-S16
3 Dahlbäck B. Pro- and anticoagulant properties of factor V in pathogenesis of thrombosis and bleeding disorders. Int J Lab Hematol 2016; 38 (Suppl. 01) 4-11
4 Cramer TJ, Gale AJ. The anticoagulant function of coagulation factor V. Thromb Haemost 2012; 107 (01) 15-21
5 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31 (15) 3777-3785
6 Tabibian S, Shiravand Y, Shams M. et al. A comprehensive overview of coagulation factor V and congenital factor V deficiency. Semin Thromb Hemost 2019; 45 (05) 523-543
7 Tinholt M, Stavik B, Tekpli X. et al. Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer. OncoImmunology 2020; 9 (01) 1824644
8 Tinholt M, Garred Ø, Borgen E. et al. Subtype-specific clinical and prognostic relevance of tumor-expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study. J Thromb Haemost 2018; 16 (07) 1347-1356
9 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
10 Testa U, Castelli G, Pelosi E. Breast cancer: a molecularly heterogenous disease needing subtype-specific treatments. Med Sci (Basel) 2020; 8 (01) E18
11 Harbeck N, Penault-Llorca F, Cortes J. et al. Breast cancer. Nat Rev Dis Primers 2019; 5 (01) 66
12 Szymiczek A, Lone A, Akbari MR. Molecular intrinsic versus clinical subtyping in breast cancer: a comprehensive review. Clin Genet 2020; 99 (05) 613-637
13 Hilton HN, Clarke CL, Graham JD. Estrogen and progesterone signalling in the normal breast and its implications for cancer development. Mol Cell Endocrinol 2018; 466: 2-14
14 Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J. The many faces of estrogen signaling. Biochem Med (Zagreb) 2014; 24 (03) 329-342
15 Ayaz G, Yasar P, Olgun CE. et al. Dynamic transcriptional events mediated by estrogen receptor alpha. Front Biosci 2019; 24: 245-276
16 Lipovka Y, Konhilas JP. The complex nature of oestrogen signalling in breast cancer: enemy or ally?. Biosci Rep 2016; 36 (03) e00352
17 Lung DK, Reese RM, Alarid ET. Intrinsic and extrinsic factors governing the transcriptional regulation of ESR1. Horm Cancer 2020; 11 (3–4): 129-147
18 Dahm AE, Eilertsen AL, Goeman J. et al. A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women. Thromb Res 2012; 130 (01) 45-51
19 Andresen MS, Ali HO, Myklebust CF. et al. Estrogen induced expression of tissue factor pathway inhibitor-2 in MCF7 cells involves lysine-specific demethylase 1. Mol Cell Endocrinol 2017; 443: 80-88
20 Farré D, Roset R, Huerta M. et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res 2003; 31 (13) 3651-3653
21 Messeguer X, Escudero R, Farré D, Núñez O, Martínez J, Albà MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 2002; 18 (02) 333-334
22 Nagy Á, Lánczky A, Menyhárt O, Győrffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep 2018; 8 (01) 9227
23 Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput Struct Biotechnol J 2021; 19: 4101-4109
24 Nathan MR, Schmid P. A review of fulvestrant in breast cancer. Oncol Ther 2017; 5 (01) 17-29
25 Sharma BK, Flick MJ, Palumbo JS. Cancer-associated thrombosis: a two-way street. Semin Thromb Hemost 2019; 45 (06) 559-568
26 Gran OV, Smith EN, Brækkan SK. et al. Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism. Haematologica 2016; 101 (09) 1046-1053
27 Kurozumi S, Matsumoto H, Kurosumi M. et al. Prognostic significance of tumour-infiltrating lymphocytes for oestrogen receptor-negative breast cancer without lymph node metastasis. Oncol Lett 2019; 17 (03) 2647-2656
28 Ochsner SA, Abraham D, Martin K. et al. The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways. Sci Data 2019; 6 (01) 252
29 Chang EC, Frasor J, Komm B, Katzenellenbogen BS. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology 2006; 147 (10) 4831-4842
30 Gong P, Madak-Erdogan Z, Li J. et al. Transcriptomic analysis identifies gene networks regulated by estrogen receptor α (ERα) and ERβ that control distinct effects of different botanical estrogens. Nucl Recept Signal 2014; 12: e001
31 Ali HO, Stavik B, Myklebust CF. et al. Oestrogens downregulate tissue factor pathway inhibitor through oestrogen response elements in the 5′-flanking region. PLoS One 2016; 11 (03) e0152114
32 Mandal S, Davie JR. Estrogen regulated expression of the p21 Waf1/Cip1 gene in estrogen receptor positive human breast cancer cells. J Cell Physiol 2010; 224 (01) 28-32
33 Anderson I, Gorski J. Estrogen receptor alpha interaction with estrogen response element half-sites from the rat prolactin gene. Biochemistry 2000; 39 (13) 3842-3847
34 Platet N, Cunat S, Chalbos D, Rochefort H, Garcia M. Unliganded and liganded estrogen receptors protect against cancer invasion via different mechanisms. Mol Endocrinol 2000; 14 (07) 999-1009
35 Ma H, Gollahon LS. ERα mediates estrogen-induced expression of the breast cancer metastasis suppressor gene BRMS1. Int J Mol Sci 2016; 17 (02) E158
36 Liu Y, Liao XW, Qin YZ, Mo XW, Luo SS. Identification of F5 as a prognostic biomarker in patients with gastric cancer. BioMed Res Int 2020; 2020: 9280841
37 Cotreau MM, Chennathukuzhi VM, Harris HA. et al. A study of 17beta-estradiol-regulated genes in the vagina of postmenopausal women with vaginal atrophy. Maturitas 2007; 58 (04) 366-376
38 Movérare S, Skrtic S, Lindberg MK, Dahlman-Wright K, Ohlsson C. Estrogen increases coagulation factor V mRNA levels via both estrogen receptor-alpha and -beta in murine bone marrow/bone. Eur J Endocrinol 2004; 151 (02) 259-263

Supplementary Material

Supplementary Material