Effect of estradiol and antiestrogens on cholesterol biosynthesis in hormone-dependent and -independent breast cancer cell lines

Cypriani, Benoit; Tabacik, Christiane; Descomps, Bernard

doi:10.1016/s0005-2728(88)80077-x

Cited by 15 publications

(12 citation statements)

References 27 publications

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“…We have excluded the possibility that cells metabolically convert ␤-estradiol to a more potent MDR inhibitor by demonstrating a direct correlation between MDR activity and steroid hydrophobicity that includes ␤-estradiol. Estrogen has been shown to stimulate cholesterol biosynthesis in estrogen-sensitive cells (34) by activating 3-hydroxy-␤-methylglutaryl-CoA reductase activity (35). This stimulation appears to involve activation of the estrogen receptor since stimulation: 1) takes many hours, 2) occurs at nanomolar estrogen concentrations, and 3) occurs only in estrogen-sensitive cells.…”

Section: Fig 8 Effect Of Lanosterol Demethylase and Acat Inhibitorsmentioning

confidence: 99%

Role of Multidrug Resistance P-glycoproteins in Cholesterol Biosynthesis

Metherall

Waugh

1996

Journal of Biological Chemistry

103

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Multidrug resistance (MDR) P-glycoproteins were first recognized for their ability to catalyze ATP-dependent efflux of cytotoxic agents from tumor cells when overexpressed. Despite extensive study, little is known about the normal substrate(s) and normal cellular function of these proteins. In the accompanying manuscript (Metherall, J. E., Waugh, K., and Li, H. (1996) J. Biol. Chem. 271, 2627-2633), we demonstrate that progesterone inhibits cholesterol biosynthesis, causing the accumulation of a number of cholesterol precursors. In the current manuscript, we use several criteria to show that the progesterone receptor is not involved in this inhibition. Rather, we demonstrate that progesterone inhibits cholesterol biosynthesis by interfering with MDR activity. We show that a steroid hormone's ability to inhibit cholesterol biosynthesis is correlated with: 1) its general hydrophobicity and 2) its ability to inhibit MDR activity. The only exception to this finding is ␤-estradiol, which is a more potent inhibitor of cholesterol biosynthesis than expected based solely on hydrophobicity and MDR inhibition. We further demonstrate that nonsteroidal inhibitors of MDR also inhibit cholesterol biosynthesis. Since MDR activity is required for esterification of LDL-derived cholesterol (P. DeBry and J. E. Metherall, submitted for publication), we investigated the relationship between these phenomena and show that inhibition of cholesterol esterification does not cause inhibition of cholesterol biosynthesis and that inhibition of cholesterol biosynthesis does not cause inhibition of cholesterol esterification. We propose a model in which MDR is required for transport of sterols from the plasma membrane to the endoplasmic reticulum (ER). Inhibiting this transport prevents cholesterol esterification and cholesterol biosynthesis by preventing sterol substrates from reaching ER-resident enzymes.

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Section: Fig 8 Effect Of Lanosterol Demethylase and Acat Inhibitorsmentioning

confidence: 99%

Role of Multidrug Resistance P-glycoproteins in Cholesterol Biosynthesis

Metherall

Waugh

1996

Journal of Biological Chemistry

103

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“…Its metabolite hydroxytamoxifen completely inhibited cholesterol synthesis in BT20 cells. Tamoxifen appears to control cholesterol synthesis at the level of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, subsequently reducing lanosterol demethylation and C-27 steroid conversion into cholesterol [18].…”

Section: Discussionmentioning

confidence: 99%

Serum cholesterol reduction with tamoxifen

Schapira

Kumar

Lyman

1990

Breast Cancer Res Tr

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The serum cholesterol levels of 123 consecutively and newly diagnosed women with Stage I and II breast cancer taking tamoxifen were compared with a control group of 81 consecutively newly diagnosed women with Stage I and II breast cancer who were not taking a hormonal treatment or supplement. Other factors that were evaluated were age, menopausal status, tumor size, weight, height, Quetelet index, and smoking and alcohol intake history. The mean cholesterol change in patients on tamoxifen (34.2 +/- 3.6 mg/dl) was significantly greater than controls (1.0 +/- 4.1 mg/dl) (P less than 0.001). Serum cholesterol fell by more than 10 mg/dl in 72.9% of women on tamoxifen vs. 35.1% of controls and by more than 40 mg/dl in 39.9% of women on tamoxifen vs. 12.6% of controls. Multivariate analysis revealed that tamoxifen administration (P less than 0.0001), initial cholesterol level (P = 0.001), and age (P = 0.04) were significant factors in producing a decrease in serum cholesterol. The administration of tamoxifen as adjuvant therapy to women with newly diagnosed breast cancer resulted in a significant fall in serum cholesterol. This effect of tamoxifen on the serum cholesterol may prove to be an additional benefit in the form of reduced cardiovascular risk in these women.

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“…2) have also been successfully used to decipher the pharmacological role of the AEBS in the anticancer actions of Tam. Like Tam, PBPE was reported to inhibit cholesterol biosynthesis in BC cells [7,20,21] and induce cancer cell death and differentiation in different cancer cell models [8,13e15,17,22e27]. Further investigations revealed that both Tam and PBPE inhibit the 3b-hydroxysteroid-D 8 ,D 7 -isomerase (D8D7I/ EBP) in BC cells and induce the intracellular accumulation of zymostenol (cholest-8-ene-3bol) which itself is not detectable at the basal level in cells [7,26,27].…”

Section: The Aebs Is a Hetero-oligomeric Complex Involved In Cholestementioning

confidence: 99%