Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism.

Bruno Payré 1, 2 Philippe De Medina 2, 3 Nadia Boubekeur 2 Loubna Mhamdi 2 Justine Bertrand-Michel 4 François Tercé 5 Isabelle Fourquaux 1 Dominique Goudounèche 1 Michel Record 2 Marc Poirot 2 Sandrine Silvente-Poirot 2
1 CMEAB - Centre de Microscopie Électronique Appliquée à la Biologie
2 Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique
Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Institut Claudius Regaud
3 Département de chimie
4 Plateau de lipidomique
5 Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150)
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.
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Molecular Cancer Therapeutics, American Association for Cancer Research, 2008, 7 (12), pp.3707-18. 〈10.1158/1535-7163.MCT-08-0507〉
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http://www.hal.inserm.fr/inserm-00519145
Contributeur : Marc Poirot <>
Soumis le : samedi 18 septembre 2010 - 15:12:57
Dernière modification le : mardi 11 septembre 2018 - 16:20:02

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Bruno Payré, Philippe De Medina, Nadia Boubekeur, Loubna Mhamdi, Justine Bertrand-Michel, et al.. Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism.. Molecular Cancer Therapeutics, American Association for Cancer Research, 2008, 7 (12), pp.3707-18. 〈10.1158/1535-7163.MCT-08-0507〉. 〈inserm-00519145〉

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