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.
Highlights
The microsomal antiestrogen-binding site (AEBS) was first described in the 1980s as a high-affinity binding site for tamoxifen, distinct from the estrogen receptors (ER; ref. 1)
To gain more insights into the antiproliferative action of AEBS ligands, we have carried out cell cycle and morphologic studies on MCF-7 cells treated with the selective AEBS ligand PBPE or with tamoxifen
The objective of our work was to define the nature of the growth control of breast cancer cells mediated by AEBS ligands and to determine if the metabolism of cholesterol was involved in this effect
Summary
The microsomal antiestrogen-binding site (AEBS) was first described in the 1980s as a high-affinity binding site for tamoxifen, distinct from the estrogen receptors (ER; ref. 1). The microsomal antiestrogen-binding site (AEBS) was first described in the 1980s as a high-affinity binding site for tamoxifen, distinct from the estrogen receptors Structure-affinity studies revealed that the AEBS, as opposed to the ER, does not bind estrogens and antiestrogens devoid of a protonable amino-ethoxy side chain but binds selective ER modulators (SERM) such as tamoxifen and raloxifene [2, 3]. The identification of diphenylmethane derivatives of tamoxifen that selectively target the AEBS, such as PBPE and DPPE, enabled the functions and pharmacology of the AEBS to be studied [4, 5]. PBPE and DPPE are not inhibitors of other known targets for tamoxifen such as protein kinase C, calmodulin, or acyl-coenzyme A:cholesterol acyltransferase activities [3, 6]. We and others have reported that the AEBS may account for the antiproliferative and cytotoxic activity of its cognate ligands, but there has been little work done on the nature of the growth control induced by these ligands [7, 8]
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