The Nuclear Oxysterol Receptor LXRα Is Expressed in the Normal Human Breast and in Breast Cancer

Vigushin, David M.; Dong, Yi; Inman, Lindsey; Peyvandi, N.; Alao, John P.; Sun, Chao; Ali, Simak; Niesor, Eric J.; Bentzen, C.; Coombes, R. Charles

doi:10.1385/mo:21:2:123

Cited by 25 publications

(15 citation statements)

References 29 publications

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“…This is the first study to report these observations in human ovarian carcinoma cells. However, the antineoplastic properties of LXR agonists have been demonstrated in other human carcinomas such as breast and prostate [12-14]. LXRs are nuclear receptors that first were discovered to have a regulatory function in control of lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

et al. 2010

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BackgroundOvarian cancer is the most common cause of cancer related death from gynecologic tumors in the United States. The insidious nature of the disease precludes early diagnosis, therefore surgical debulking and chemotherapy are considered as standard treatment modalities for advanced stages. We investigated the effect of the LXR agonist, T0901317, on ovarian cancer cell proliferation and apoptosis as a potential therapeutic agent.ResultsT0901317 treatment resulted in a significant (P <0.001) inhibition of cell proliferation in a time- and dose-dependent manner in CaOV3, SKOV3 and A2780 cells. Western blot analysis demonstrated an induction of p21 and p27 with a concominant reduction in phospho-RB protein levels. Cell cycle analysis demonstrated a significant (P <0.001) arrest in the G1 cell cycle phase. Significant induction of Caspase-3 and BAX gene expression occurred with treatment. Induction of apoptosis was confirmed by significant (P < 0.001) elevation of caspase activity on FACS analysis, caspase-glo assay, BAX protein induction and decreased caspase 3 precursor protein expression on Western blot analysis. LXR α/β knockdown experiments did not reverse the anti-proliferative and cytotoxic effects of T0901317.ConclusionsThe LXR agonist, T0901317, significantly suppresses cell proliferation and induces programmed cell death in a dose- and time-dependent manner. Our results indicate that T0901317 induces its anti-proliferative and cytotoxic effects via an LXR-independent mechanism.

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Section: Discussionmentioning

confidence: 99%

Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

et al. 2010

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“…Liver X receptors have recently been shown to be involved in the normal physiologic processes of lactation (30). Moreover, the liver X receptor a subtype has been reported to be expressed in normal human breast, whereas its expression varied in breast cancer cell lines (31). We have observed that pharmacologic activators of liver X receptors such as T0901317 stimulate lipogenesis in MCF-7 cells (data not shown), suggesting that they might participate in the breast cell differentiation processes stimulated by AEBS ligands.…”

Section: Discussionmentioning

confidence: 99%

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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“…This may be an additional mechanism by which PS may affect estrogen levels, cell division and breast cancer risk. Accumulating evidence has not only demonstrated the expression of LXR in both ER+ and ER− breast cancer cells but suggests that LXR agonists profoundly inhibit cell proliferation [93,94,95]. Mechanistically, LXR activation has been shown to down-regulate the ER while also increasing protein levels of P53 [93].…”

Section: Plant Sterols and The Liver X Receptormentioning

confidence: 99%

Plant Sterols as Anticancer Nutrients: Evidence for Their Role in Breast Cancer

Grattan

2013

Nutrients

100

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While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one’s risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. As outlined in this review, the cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions. Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role.

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The Nuclear Oxysterol Receptor LXRα Is Expressed in the Normal Human Breast and in Breast Cancer

Cited by 25 publications

References 29 publications

Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

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

Plant Sterols as Anticancer Nutrients: Evidence for Their Role in Breast Cancer

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