Mifepristone (RU486): A review

Mahajan, Damodar K.; London, Steve N.

doi:10.1016/s0015-0282(97)00189-1

Cited by 148 publications

(76 citation statements)

References 64 publications

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“…6A, GR FL). RU-486 is a hydrocortisone analogue that is able to bind to GR but inhibits the transcription of GR target genes (31). As with hydrocortisone, treatment of mouse and human mammary cells with a comparable concentration of RU-486 [$3 mmol/L hydrocortisone (1 mg/mL) compared with 5 mmol/L RU-486] resulted in decreased expression of endogenous BRCA1 (Fig.…”

Section: Eph-4 -Hc Eph-4 +Hcmentioning

confidence: 99%

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Ritter

Antonova

Mueller

2012

Molecular Cancer Research

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Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the b-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPb interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk. Mol Cancer Res; 10(4); 558-69. Ó2012 AACR. IntroductionGerm line mutations in the BRCA1 tumor suppressor contribute to familial breast tumor formation but BRCA1 mutations do not seem to occur in sporadic breast cancer tumors (1). Instead, sporadic breast tumors exhibit decreased levels of BRCA1 expression, and the degree of downregulation seems to be correlated with tumor grade, rate of tumor progression, and risk of metastasis (2-6). This implies that loss of BRCA1 function, either through decreased activity or downregulation of expression, is a critical event in the etiology of breast cancer. Phenotypically normal breast epithelial cells from individuals harboring a BRCA1 germ line mutation (a so called "one-hit" mutation accompanied by a 50% decrease in BRCA1 function) express an altered mRNA profile compared with normal cells from individuals without a BRCA1 mutation (7). This suggests that decreases in functional BRCA1

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Section: Eph-4 -Hc Eph-4 +Hcmentioning

confidence: 99%

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Ritter

Antonova

Mueller

2012

Molecular Cancer Research

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“…4A). To establish a direct link between GC signalling, upregulation of mRNA and protein levels of SR-BI and occludin, and enhancement of HCV entry, we utilized RU-486, a drug that antagonizes GC signalling by direct binding to the GC receptor 37 . Remarkably, 10 µg/ml RU-486 fully abolished stimulation of HCV cell entry by prednisolone (Fig.…”

Section: Ru-486 An Antagonist Of Gc Signalling Counteracts Upregulamentioning

confidence: 99%

Glucocorticosteroids Increase Cell Entry by Hepatitis C Virus

et al. 2010

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“…Antagonism of GRs has been shown to modulate several physiological systems, including the central nervous system, immune response, metabolism, digestive, renal, and reproductive systems (Lu et al, 2006). The combination of mifepristone (Mifeprex) with misoprostol (Cytotec), a prostaglandin analog, is currently FDA approved for the termination of early pregnancy (Lu et al, 2006;Mahajan and London, 1997). The anti-GC activity of mifepristone has made it a potential treatment for Cushing's syndrome (Johanssen and Allolio, 2007) and neurological and psychological disorders (DeBattista and Belanoff, 2006;Gallagher and Young, 2006;Gallagher et al, 2005Gallagher et al, , 2008Wulsin et al, 2010;Young, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

Simms

Haass‐Koffler

Bito-Onon

et al. 2011

Neuropsychopharmacol

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Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol-and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucroseseeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanolseeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

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Mifepristone (RU486): A review

Cited by 148 publications

References 64 publications

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Glucocorticosteroids Increase Cell Entry by Hepatitis C Virus

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

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