title: 5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of tamoxifen in breast cancer cells.
abstract: Tamoxifen (Tam) is a selective estrogen receptor modulator (SERM) that remains one of the major drugs used in the hormonotherapy of breast cancer (BC). In addition to its SERM activity, we recently showed that the oxidative metabolism of cholesterol plays a role in its anticancer pharmacology. We established that these effects were not regulated by the ER but by the microsomal antiestrogen binding site/cholesterol-5,6-epoxide hydrolase complex (AEBS/ChEH). The present study aimed to identify the oxysterols that are produced under Tam treatment and to define their mechanisms of action. Tam and PBPE (a selective AEBS/ChEH ligand) stimulated the production and the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC), 5,6α-epoxy-cholesterol-3β-sulfate (5,6-ECS), 5,6β-epoxy-cholesterol (5,6β-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6α-EC by SULT2B1b. We showed that only 5,6α-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXRβ. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6β-EC through an LXRβ-independent route and by 5,6-ECS through an LXRβ-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6α-EC, Tam or PBPE at a comparable level to MCF-7 cells. This study established that 5,6-EC metabolites contribute to the anticancer pharmacology of Tam and highlights a novel signaling pathway that points to a rationale for re-sensitizing BC cells to Tam and AEBS/ChEH ligands.
authors.affiliation: UMR 1037 INSERM-University Toulouse III, Cancer Research Center of Toulouse, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Segala
authors.forename: Philippe
authors.initials: P
authors.lastname: de Medina
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
authors.forename: Chiara
authors.initials: C
authors.lastname: Zerbinati
authors.forename: Michael R
authors.initials: MR
authors.lastname: Paillasse
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Noguer
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Bruno
authors.initials: B
authors.lastname: Payré
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.forename: Michel
authors.initials: M
authors.lastname: Record
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015238:Sulfotransferases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: C583504:1-(2-(4-benzylphenoxy)ethyl)pyrrolidin-HCl; C119784:5,6-epoxycholesterol; D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D020845:Selective Estrogen Receptor Modulators; D014280:Triglycerides; D013629:Tamoxifen; D002784:Cholesterol; D015238:Sulfotransferases; C433248:SULT2B1 protein, human; D004851:Epoxide Hydrolases; C019885:cholesterol-5 alpha,6 alpha-epoxide hydrase