title: Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism.
abstract: The microsomal antiestrogen-binding site (AEBS) is a high-affinity membranous binding site for the antitumor drug tamoxifen that selectively binds diphenylmethane derivatives of tamoxifen such as PBPE and mediates their antiproliferative properties. The AEBS is a hetero-oligomeric complex consisting of 3beta-hydroxysterol-Delta8-Delta7-isomerase and 3beta-hydroxysterol-Delta7-reductase. High-affinity AEBS ligands inhibit these enzymes leading to the massive intracellular accumulation of zymostenol or 7-dehydrocholesterol (DHC), thus linking AEBS binding to the modulation of cholesterol metabolism and growth control. The aim of the present study was to gain more insight into the control of breast cancer cell growth by AEBS ligands. We report that PBPE and tamoxifen treatment induced differentiation in human breast adenocarcinoma cells MCF-7 as indicated by the arrest of cells in the G0-G1 phase of the cell cycle, the increase in the cell volume, the accumulation and secretion of lipids, and a milk fat globule protein found in milk. These effects were observed with other AEBS ligands and with zymostenol and DHC. Vitamin E abrogates the induction of differentiation and reverses the control of cell growth produced by AEBS ligands, zymostenol, and DHC, showing the importance of the oxidative processes in this effect. AEBS ligands induced differentiation in estrogen receptor-negative mammary tumor cell lines SKBr-3 and MDA-MB-468 but with a lower efficiency than observed with MCF-7. Together, these data show that AEBS ligands exert an antiproliferative effect on mammary cancer cells by inducing cell differentiation and growth arrest and highlight the importance of cholesterol metabolism in these effects.
authors.affiliation: INSERM, U-563, Section métabolisme, oncogenèse et différenciation cellulaire, Centre de Physiopathologie de Toulouse Purpan, Institut Claudius Regaud, 24 rue du Pont Saint Pierre, F-31052 Toulouse Cedex, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Payré
authors.forename: Philippe
authors.initials: P
authors.lastname: de Medina
authors.forename: Nadia
authors.initials: N
authors.lastname: Boubekeur
authors.forename: Loubna
authors.initials: L
authors.lastname: Mhamdi
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: François
authors.initials: F
authors.lastname: Tercé
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fourquaux
authors.forename: Dominique
authors.initials: D
authors.lastname: Goudounèche
authors.forename: Michel
authors.initials: M
authors.lastname: Record
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008861:Microsomes / Q000378:metabolism*; D008894:Milk Proteins / Q000737:chemistry; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D020847:Estrogen Receptor Modulators; D008024:Ligands; D008055:Lipids; D008894:Milk Proteins; D013629:Tamoxifen; D002784:Cholesterol