Response-Specific and Ligand Dose-Dependent Modulation of Estrogen Receptor (ER) α Activity by ERβ in the Uterus

Frasor, Jonna; Barnett, Daniel H.; Danes, Jeanne M.; Hess, Rüdiger; Parlow, Albert F.; Katzenellenbogen, Benita S.

doi:10.1210/en.2002-0143

Cited by 214 publications

(175 citation statements)

References 32 publications

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“…and DPN (1.0 mg/kg/inj, i.p.) correspond to effective doses that have been previously reported (Harris et al, 2002;Frasor et al, 2003;Lund et al, 2005;Le Saux and Di Paolo, 2005;Le Saux et al, 2006). These previous reports indicate that, in some cases, selective activation of ERa or ERb by a 1.0 mg/kg dose of PPT (ERa) or DPN (ERb) produced similar effects, such as in the striatum, where both increased preproenkephalin mRNA levels (Le Saux and Di Paolo, 2005).…”

Section: Drugssupporting

confidence: 82%

“…In contrast, rats treated with a 1.0 mg/kg dose of the ERa-selective agonist PPT showed reinstatement of active lever responding that resembled that of the OVX + DMSO controls, indicating that the ERa activation produced by this dose of PPT did not influence the amount of cocaine-seeking behavior. The dose of PPT and DPN that we used in this study (1.0 mg/kg) is biologically effective (Harris et al, 2002;Frasor et al, 2003;Lund et al, 2005) and selectively activates the ERa and ERb subtypes, respectively (Lund et al, 2005). Furthermore, at the 1.0 mg/kg dose, both compounds can reach the brain within 30 min of peripheral administration (Harris et al, 2002;Lund et al, 2005), which corresponds to the timing of the treatment regimen used in this study.…”

Section: Discussion Er Activation and Active Lever Responding During mentioning

confidence: 96%

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Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

Larson

Carroll

2006

Neuropsychopharmacol

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Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor a (ERa) and b (ERb) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERa/b agonist estradiol benzoate (EB), the ERa-selective agonist, propyl-pyrazole-triol (PPT), the ERb-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX + DMSO controls. Selective activation of ERb with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERa with PPT did not affect cocaineseeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERb.

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Section: Drugssupporting

confidence: 82%

Section: Discussion Er Activation and Active Lever Responding During mentioning

confidence: 96%

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

Larson

Carroll

2006

Neuropsychopharmacol

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“…ERα ligands show significant uterotrophic activity while ERβ ligands are neither uterotrophic nor mammotrophic (Frasor et al, 2003;Harris et al, 2003;Hegele-Hartung et al, 2004;Hillisch et al, 2004). In addition, preliminary evidence obtained from immortalized normal HC11 mouse mammary gland cells showed ERα ligand-stimulated proliferation and expression of proliferation markers whereas a selective ERβ ligand inhibited proliferation and induced apoptosis (Helguero et al, 2005).…”

Section: Ermentioning

confidence: 99%

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

Saarinen

Bingham²,

Lorenzetti

et al. 2006

Genes Nutr

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“…Microarray analysis of endogenous gene expression illustrates both common and divergent genes regulated by ERα versus ERβ in the reproductive tissues of mice treated with isoformspecific ligands [27,28], or in bone from ERα (ERKO) and ERβ (BERKO) gene-disrupted mice [29]. Effects of ERβ-E2 on gene expression were generally lower than ERα-E2 [29].…”

Section: Erα and Erβ Activity -Homodimers And Heterodimers A Transcrmentioning

confidence: 99%

ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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Response-Specific and Ligand Dose-Dependent Modulation of Estrogen Receptor (ER) α Activity by ERβ in the Uterus

Cited by 214 publications

References 32 publications

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

ERβ in breast cancer—Onlooker, passive player, or active protector?

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