title: Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms.
abstract: Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Gérard
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Mestdagt
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Ekaterine
authors.initials: E
authors.lastname: Tskitishvili
authors.affiliation: Gynaecological Endocrinology Unit, Paris Descartes University, Hôpitaux Universitaires, Paris, France.
authors.forename: Laudine
authors.initials: L
authors.lastname: Communal
authors.affiliation: Gynaecological Endocrinology Unit, Paris Descartes University, Hôpitaux Universitaires, Paris, France.|INSERM U938, Université Pierre et Marie Curie, Paris.
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Silva
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, University of Toulouse, UPS, Toulouse, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, University of Toulouse, UPS, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Péqueux
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004953:Estetrol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects* / Q000379:methods*; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004953:Estetrol
keywords: SERM; breast cancer; estetrol; estrogen receptor; menopause