Tamoxifen and toremifene lower serum cholesterol by inhibition of delta 8-cholesterol conversion to lathosterol in women with breast cancer.

Gylling, Helena; Pyrhönen, Seppo; Mäntylä, Eero; Mäenpää, Hanna; Kangas, Lauri; Miettinen, T. A.

doi:10.1200/jco.1995.13.12.2900

Cited by 95 publications

(50 citation statements)

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“…Other investigators have shown that tamoxifen interferes with synthesis of cholesterol in hepatic cells by inhibition of the conversion of precursor lipids 31 and that tamoxifen is a potent inhibitor of sterol Δ8-isomerase, a cholesterol synthetic enzyme. 32 Although our data suggest that the mechanism of tamoxifen's lipid-lowering effect may be mediated by ERs, it is not known if these receptors influence Δ-isomerase activity, or whether other downstream signaling mechanisms are involved. These remain important subjects for future research.…”

Section: Discussionmentioning

confidence: 80%

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Ntukidem

Nguyen

Stearns

et al. 2007

Clin Pharmacol Ther

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Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5mg/dl (13.5-33.5mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and highdensity lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.The use of exogenous estrogen to prevent cardiovascular disease in women has been a subject of controversy since data from the Women's Health Initiative trial suggested that postmenopausal women might experience a greater number of cardiovascular events when treated with hormone replacement therapy. 1 There is large interindividual variability in the response to estrogens, and Herrington et al. 2 have suggested that this may be due in part to genetic variants in the estrogen receptors (ERs). As the Women's Health Initiative study made prospective study of the effects of estrogens difficult and as the selective estrogen response modifier tamoxifen acts as an exogenous estrogen on serum lipids, we elected to study the effects of tamoxifen on serum lipids and to test the hypothesis that genetic variants are associated with variability in response. © 2007 American Society for Clinical Pharmacology and TherapeuticsCorrespondence to: DF Hayes, hayesdf@umich.edu. 5 Current address: Division of Hematology/Oncology, Department of Medicine, Ohio State University, Columbus, Ohio, USA. CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTamoxifen is a selective ER modulator widely used in the treatment of ER-or progesterone receptor-positive breast cancer, and it is the only agent approved for the prevention of the disease. [3][4][5][6] As a selective ER modulator, tamoxifen has both estrogenic and anti-estrogenic effects depending on the target tissue. Tamoxifen effects on serum lipid concentration are largely similar to those of estrogen. 7,8 Tamoxifen is documented to cause a reduction in serum total and low-density lipoprotein (LDL), but data on high-density lipoprotein (HDL) and triglycerides have not been consistent. [9][10][11][12][13][14] The effects of tamoxifen vary from patient to patient, and this variabili...

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Section: Discussionmentioning

confidence: 80%

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Ntukidem

Nguyen

Stearns

et al. 2007

Clin Pharmacol Ther

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“…Earlier studies reported that tamoxifen induced the accumulation of zymostenol in the blood of patients (9). These data, coupled with the fact that the AEBS bound oxygenated derivatives of sterols such as 7-ketocholesterol, 6-ketocholestanol, and 7-ketocholestanol with high affinity (10,11), opened up the possibility of a link between the binding to the AEBS and the oxidative metabolism of cholesterol.…”

Section: Introductionmentioning

confidence: 90%

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

Payré

Médina

Boubekeur

et al. 2008

Molecular Cancer Therapeutics

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The microsomal antiestrogen-binding site (AEBS) is a highaffinity 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 3B-hydroxysterol-# 8 -# 7 -isomerase and 3B-hydroxysterol-# 7 -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 G 0 -G 1 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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“…In this context, an attractive property of SERMs is their ability to improve cardiovascular risk factors. Toremifene reduces both total and low-density lipoprotein (LDL) cholesterol and increases high-density lipoprotein (HDL) cholesterol ( Figure 3) [47][48][49][50] . Particularly persuasive are the results from a crossover trial in which 197 women receiving adjuvant therapy with toremifene or tamoxifen were monitored for lipid levels [51] .…”

Section: Lipidsmentioning

confidence: 99%

Toremifene in the treatment of breast cancer

Mustonen¹

2014

WJCO

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Core tip: Toremifene is safe and effective in the treatment of breast cancer. Toremifene and tamoxifen are equivalently effective in the treatment of breast cancer, although some studies show an advantage for toremifene. Safety and tolerability is also broadly equivalent, although toremifene may cause fewer uterine neoplasms, serious vascular adverse events and has a more beneficial effect on plasma lipids than does tamoxifen.Mustonen MVJ, Pyrhönen S, Kellokumpu-Lehtinen PL. Toremifene in the treatment of breast cancer.

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Tamoxifen and toremifene lower serum cholesterol by inhibition of delta 8-cholesterol conversion to lathosterol in women with breast cancer.

Cited by 95 publications

References 0 publications

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

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

Toremifene in the treatment of breast cancer

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