Estrogen receptor α and β subtype expression and transactivation capacity are differentially affected by receptor-, hsp90- and immunophilin-ligands in human breast cancer cells

Gougelet, Angélique; Bouclier, Céline; Marsaud, Véronique; Maillard, Sébastien; Mueller, Stefan O.; Korach, Kenneth S.; Renoir, Jack‐Michel

doi:10.1016/j.jsbmb.2005.01.018

Cited by 51 publications

(48 citation statements)

References 62 publications

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“…During our preparation of the manuscript, deGraffenried et al (2004) and Gougelet et al (2005) reported that transactivation of ER is inhibited by temsirolimus and rapamycin respectively, which is consistent with our results. Our study utilizing the endogenous ER of MCF-7 cells as well as transiently transfected Gal4-ERa(242), which comprises the ER dimerization domain and ligand-binding domain, is not only in agreement with their observation, but also identified that the dimerization domain and ligand-binding domains are sufficient to confer a temsirolimus effect (data not shown).…”

Section: Discussionsupporting

confidence: 92%

“…It is worth noting that two recent studies reported weak apoptosis associated with rapamycin treatment, which is not evident in our study. The difference may be due to either the pharmacological difference between rapamycin and temsirolimus or different concentrations used in the studies (Basso et al 2005, Gougelet et al 2005.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, synergistic inhibition was observed when RAD001 was combined with the aromatase inhibitor, letrozole (Boulay et al 2005). Rapamycin and cyclosporine were recently reported to target both ERa and ERb to proteasome-mediated proteolysis, resulting in decreased estradiol (E2)-induced ER transactivation (Gougelet et al 2005). Interestingly, a farnesyl transferase inhibitor, lonafarnib, was shown to potentiate Tam-mediated apoptosis in MCF-7 breast cancer cells (Basso et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

Sadler¹,

Gavriil²,

Annable³

et al. 2006

Endocr Relat Cancer

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The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-a (ERa) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxy-tamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERa as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

Sadler¹,

Gavriil²,

Annable³

et al. 2006

Endocr Relat Cancer

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“…How they are targeted is not discerned, but most contain at least one F/LXXLL motif and/or are bound by Hsp90/70 in the cytosol. Unliganded ERβ, as a member of the nuclear receptor family, is regulated through a molecular chaperone-complex that includes Hsp90 and Hsp70 (Cheung and Smith, 2000;Gougelet et al, 2005). As a client protein, Hsp90 helps maintain the receptor in a quiescent state by binding the ligand binding domain, and thereby assists in normal folding to maintain its native status and prevents degradation (Smith et al, 1998;Cheung and Smith, 2000;Pratt and Toft, 2003).…”

Section: Mitochondrial Trafficking Of Erβmentioning

confidence: 99%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

135

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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“…L'inhibition de la liaison de la hsp90 entraine une dégradation des REs par le protéasome (Roe et al, 1999 ;Maloney et Workman, 2002 ;Gougelet et al, 2005). (Brzozowski et al, 1997 ;Picke et al, 2000).…”

Section: Mécanismes Moléculaires D'action Des Resunclassified

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

et al. 2012

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Titre : La 7β-hydroxy-épiandrostérone dans des modèles in vitro de cancer du sein : effets anti-estrogéniques et rôle des récepteurs des estrogènes. La 7β-hydroxy-épiandrostérone, stéroïde endogène dérivant de la DHEA, présente des propriétés antiinflammatoires. En effet, elle module la voie des prostaglandines (PGs) en inhibant la production de la PGE2 pro-inflammatoires et en augmentant la production de la 15-Deoxy-∆ 12,14 -PGJ2 cyto-protectrice in vivo et in vitro. Les faibles doses de 7β-hydroxy-épiandrostérone (1nM, 10nM, 100nM) pour lesquelles ces effets sont observés, suggèrent une liaison à un récepteur spécifique. L'inflammation et la production des PGs jouent un rôle important dans le développement et la prolifération des tumeurs mammaires estrogéno-dépendantes. Le 17β-estradiol (E2), en se fixant sur les récepteurs des estrogènes (REs), induit la production de PGE2 et la prolifération cellulaire dans ces cellules tumorales. De ce fait, notre objectif était de tester les effets de la 7β-hydroxy-épiandrostérone sur la prolifération (comptage avec exclusion au bleu trypan), le cycle cellulaire et l'apoptose (cytométrie de flux) dans les lignées cellulaires de cancer du sein MCF-7 (REα+, REβ+, GPR30+) et MDA-MB-231 (REα-, REβ+, GPR30+) et d'identifier une(des) cible(s) potentielle(s) dans ces cellules (transactivation) et dans des cellules négatives pour les REs nucléaires SKBr3 (GPR30+) (études de prolifération). Cette étude a montré que la 7β-hydroxy-épiandrostérone exerce des effets anti-estrogéniques dans les cellules MCF-7 et MDA-MB-231 associés à une inhibition de la prolifération et un arrêt du cycle cellulaire. Les études de transactivation et de prolifération avec les agonistes spécifiques des REs ont montré une interaction avec le REβ. De plus, les résultats des études de proliférations sur les trois lignées cellulaires suggèrent que la 7β-hydroxy-épiandrostérone pourrait également interagir avec le GPR30. Ces résultats indiquent que ce stéroïde androgène agit comme un anti-estrogène. De plus, c'est la première fois qu'un stéroïde androgène à faible dose montre une action anti-proliférative dans des lignées de cancers du sein. De études ultérieures restent à réaliser afin de mieux comprendre ces effets observés. Mots clés : 7β-hydroxy-épiandrostérone, récepteurs des estrogènes, lignées de carcinomes mammaires, prolifération, transactivationThe DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines 7β-hydroxy-epiandrosterone, an endogenous androgenic derivative of DHEA, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-∆ 12,14 -PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7β-hydroxy-epiandrosterone (1-100 nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogendependent mammary cancers. Estrogen induced PGE2 ...

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Estrogen receptor α and β subtype expression and transactivation capacity are differentially affected by receptor-, hsp90- and immunophilin-ligands in human breast cancer cells

Cited by 51 publications

References 62 publications

Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

Estrogen actions on mitochondria—Physiological and pathological implications

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

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