title: Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.
abstract: Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria, Pantarhei Bioscience, Zeist 3701, The Netherlands, Department of Pathology, LKH Amstetten, Amstetten 3300, Austria, Department of Pathology, Medical University of Vienna, Vienna 1090, Austria, and Department of Pathology, Medical University of Graz, Graz 8036, Austria christian.singer@meduniwien.ac.at.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.affiliation: Pantarhei Bioscience, Zeist 3701, The Netherlands.
authors.forename: Herjan J T Coelingh
authors.initials: HJ
authors.lastname: Bennink
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria, Pantarhei Bioscience, Zeist 3701, The Netherlands, Department of Pathology, LKH Amstetten, Amstetten 3300, Austria, Department of Pathology, Medical University of Vienna, Vienna 1090, Austria, and Department of Pathology, Medical University of Graz, Graz 8036, Austria.
authors.forename: Camilla
authors.initials: C
authors.lastname: Natter
authors.affiliation: Department of Pathology, LKH Amstetten, Amstetten 3300, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna 1090, Austria, and.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Rudas
authors.affiliation: Department of Pathology, Medical University of Graz, Graz 8036, Austria.
authors.forename: Farid
authors.initials: F
authors.lastname: Moinfar
authors.affiliation: Pantarhei Bioscience, Zeist 3701, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Appels
authors.affiliation: Pantarhei Bioscience, Zeist 3701, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Visser
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria, Pantarhei Bioscience, Zeist 3701, The Netherlands, Department of Pathology, LKH Amstetten, Amstetten 3300, Austria, Department of Pathology, Medical University of Vienna, Vienna 1090, Austria, and Department of Pathology, Medical University of Graz, Graz 8036, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Kubista
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D004953:Estetrol / Q000008:administration & dosage*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020249:Hormone Replacement Therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D057234:Preoperative Period
chemical_list: D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D007334:Insulin-Like Growth Factor I; D005640:Follicle Stimulating Hormone; D004953:Estetrol