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Abstract
Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) α. ERR has three subtypes (α, β, and γ) expressed in estrogen-sensitive organs, including ovary, breast, and brain. No endogenous ligands of ERRs have been identified, but these receptors share a common DNA element with ERα and control estrogen-mediated gene transcription. Recent evidence suggests a role of ERRs in estrogen-related pathophysiology, but the detailed mechanisms of ERR functions in estrogen-related tissues are unclear. Using live-cell imaging with fluorescent protein labeling, we found that only ERRβ among the ERRs exhibits a punctate intranuclear pattern overlapping with ERα following 17β-estradiol (E2)-stimulation. Fluorescence recovery after photobleaching showed significant reduction of the mobility of ligand-activated ERα with co-expression of ERRβ. Fluorescence resonance energy transfer revealed that ERRβ directly interacts with ERα. The N-terminal domain of ERRβ was identified as the region that interacts with ERα. We also found a correlation between punctate cluster formation of ERα and interaction between the receptors. Expression of ERRβ significantly repressed ERα-mediated transactivity, whereas that of other ERR subtypes had no effect on the transactivity of ERα. Consistent with this finding, E2-stimulated proliferation of MCF-7 breast carcinoma cells and bcl-2 expression was significantly inhibited by expression of ERRβ. These results provide strong evidence for a suppressive effect of ERRβ on estrogen signaling through reduction of the intranuclear mobility of ERα. The findings further suggest a unique inhibitory role for ERRβ in estrogen-dependent cellular function such as cancer cell proliferation.
Highlights
The role of orphan nuclear receptor Estrogen-related receptor (ERR) in estrogen-related pathophysiology is poorly understood
Protein expression of CFP-estrogen receptor (ER)␣ and YFP-ERRs was confirmed by Western blotting from total lysates of COS-1 cells transfected with pcDNA3.1-ER␣, pECFP-ER␣, pcDNA3.1-ERRs (␣, , or ␥), or pEYFP-ERRs (␣, , or ␥)
Specific antibodies against ER␣, ERR␣, -, or -␥ were used to detect each protein at the predicted molecular mass (Fig. 1A)
Summary
The role of orphan nuclear receptor ERR in estrogen-related pathophysiology is poorly understood. Estrogen receptor (ER)2 ␣ and  are ligand-dependent transcription factors that play critical roles in diverse pathophysiological programs, including reproduction, development, homeostasis, and cancer progression [1,2,3] Another subgroup in the nuclear receptor (NR) superfamily, the estrogen-related receptors (ERRs), has strong homology to ER␣ [4, 5]. The intranuclear mobility of ligand-activated ER␣ was reduced by direct interaction with ERR Consistent with this finding, ERR repressed the transactivity of ER␣ in ERE-driven transcription and reduced proliferation of ER␣-positive breast cancer cells. These findings reveal a co-regulatory pathway of estrogen signaling by classical ER␣ and ERR, and they suggest a novel hormone-response mechanism of ligand-dependent transregulation mediated by orphan NRs
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