title: Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.
abstract: Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Gérard
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Communal
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Courtin
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Tskitishvili
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Mestdagt
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Munaut
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Gompel
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France C.Pequeux@ulg.ac.be.
authors.forename: C
authors.initials: C
authors.lastname: Péqueux
authors.affiliation: Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Foidart
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D004953:Estetrol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055815:Young Adult
chemical_list: D004965:Estrogen Antagonists; D004953:Estetrol
keywords: agonist/antagonist; contraception; estetrol; estrogen receptor alpha; mammary gland; menopause; proliferation