title: ERα dimerization: a key factor for the weak estrogenic activity of an ERα modulator unable to compete with estradiol in binding assays.
abstract: Estrothiazine (ESTZ) is a weak estrogen sharing structural similarities with coumestrol. ESTZ failed to compete with [3H]17β-estradiol ([3H]17β-E2) for binding to the estrogen receptor α (ERα), questioning its ability to interact with the receptor. However, detection by atomic force spectroscopy (AFS) of an ESTZ-induced ERα dimerization has eliminated any remaining doubts. The effect of the compound on the proliferation of ERα-positive and negative breast cancer cells confirmed the requirement of the receptor. The efficiency of ESTZ in MCF-7 cells was weak without any potency to modify the proliferation profile of estradiol and coumestrol. Growth enhancement was associated with a proteasomal degradation of ERα without substantial recruitment of LxxLL coactivators. This may be related to an unusual delay between the acquisition by the receptor of an ERE-binding capacity and the subsequent estrogen-dependent transcription. A complementary ability to enhance TPA-induced AP-1 transcription was observed, even at concentrations insufficient to activate the ERα, suggesting a partly independent mechanism. ESTZ also rapidly and transiently activated ERK1/2 likely through membrane estrogenic pathways provoking a reorganization of the actin network. Finally, the systematic absence of biological responses with an ESTZ derivative unable to induce ERα dimerization stresses the importance of this step in the action of the compound, as reported for conventional estrogens. In view of the existence of many other ERα modulators (endocrine disruptors such as, for example, pesticides, environmental contaminants or phytoestrogens) with extremely weak or similar apparent lack of binding ability, our work may appear as pilot investigation for assessing their mechanism of action.
authors.affiliation: a Laboratoire J.-C. Heuson de Cancérologie Mammaire , Université Libre de Bruxelles (U.L.B.), Institut Jules Bordet , Brussels , Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Leclercq
authors.affiliation: a Laboratoire J.-C. Heuson de Cancérologie Mammaire , Université Libre de Bruxelles (U.L.B.), Institut Jules Bordet , Brussels , Belgium.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Laïos
authors.affiliation: b Institut FEMTO-ST, CNRS UMR 6174, Université de Bourgogne Franche-Comté , Besançon , France.
authors.forename: Céline
authors.initials: C
authors.lastname: Elie-Caille
authors.affiliation: c Laboratoire Signalisation et Régulations Cellulaires , Institut de Biochimie et de Biologie Moléculaire et Cellulaire, CNRS UMR 8619, Université Paris-Sud , Orsay Cedex , France.|d INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Université d'Angers , Angers , France.
authors.forename: Denis
authors.initials: D
authors.lastname: Leiber
authors.affiliation: e Service d'Histologie et de Cytologie Expérimentale, Faculté de Médecine et de Pharmacie , Université de Mons-Hainaut , Mons , Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.affiliation: f ICB, CNRS UMR 6303, Université de Bourgogne Franche-Comté , Dijon , France.
authors.forename: Eric
authors.initials: E
authors.lastname: Lesniewska
authors.affiliation: c Laboratoire Signalisation et Régulations Cellulaires , Institut de Biochimie et de Biologie Moléculaire et Cellulaire, CNRS UMR 8619, Université Paris-Sud , Orsay Cedex , France.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Tanfin
authors.affiliation: g Département de Chimie, CNRS UMR 7203 LBM , Sorbonne Universités - UPMC Univ Paris 06, Ecole Normale Supérieure, PSL Research University , Paris , France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Jacquot
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019281:Dimerization; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D048789:Phytoestrogens; D011485:Protein Binding / Q000235:genetics; D013054:Spectrophotometry, Atomic; D013843:Thiazines / Q000008:administration & dosage* / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D048789:Phytoestrogens; D013843:Thiazines; D018808:Transcription Factor AP-1; D004958:Estradiol
keywords: Dimerization; ERK1/2; estrogen receptor; proliferation; transcription; weak estrogen