Estrogen-related receptor α as a therapeutic target in cancer

Stein, Rebecca A.; McDonnell, Donald P.

doi:10.1677/erc.1.01292

Cited by 102 publications

(41 citation statements)

References 34 publications

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“…There is mounting clinical evidence linking ERR␣ expression to tumor progression and less favorable prognoses in breast cancer patients (43,44,46,47). We have previously demonstrated that estrogens induce ERR␣ expression in MCF-7 cells, an ER␣-positive breast cancer cell line.…”

Section: Discussionmentioning

confidence: 95%

“…Interestingly, recent clinical studies implicate ERR␣ as having a potential role in breast cancer progression (43,44) based largely on its greater prevalence in ER␣-negative tumors and correlation with ErbB2, a known marker of aggressive tumors (45). Hence, positive ERR␣ expression is increasingly associated with an adverse clinical outcome and decreased chance of survival in breast cancer patients (46,47). ERR␣ may promote the growth of breast cancers by increasing local estrogen synthesis as it is reported to stimulate the expression of CYP19A1 (P450 aromatase) (48,49) and SULT2A1 (50), enzymes that contribute to estrogen biosynthesis.…”

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confidence: 99%

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Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

Kinyamu

Wang

et al. 2008

Journal of Biological Chemistry

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Estrogen-related receptor ␣ (ERR␣), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ER␣ and ER␤). The ERR␣ gene is estrogen-responsive in several mouse tissues and cell lines, and a multiple hormone-response element (MHRE) in the promoter is an important regulatory region for estrogen-induced ERR␣ gene expression. ERR␣ was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ER␣. The contribution of ERR␣ in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERR␣ gene expression and chromatin structural changes under the influence of 17␤-estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERR␣ promoter around the MHRE region and found that the MHRE resides within a single nucleosome. Local chromatin structure of the MHRE exhibited increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation upon estrogen treatment. Interestingly, estrogen-induced chromatin structural changes could be repressed by estrogen antagonist ICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells. We demonstrated, using chromatin immunoprecipitation assays, that 17␤-estradiol induces ERR␣ gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERR␣ and AP1 bind and ER␣ is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines.Estradiol (E 2 ) 2 is required for the development and function of multiple tissue types and physiological systems in mammals, and it has been implicated in a range of pathological conditions, including the initiation and progression of breast cancer (Refs.

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

Kinyamu

Wang

et al. 2008

Journal of Biological Chemistry

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“…Recent evidence also suggests a role for epigenetic modulation in the process of adipocyte differentiation. microRNA (miR) 125-a inhibits the expression of estrogen-related receptor α (ESRRA) , an orphan nuclear receptor that modulates the activity of ESR1 in some tissues (Stein & McDonnell 2006). Inhibition of miR-125a leads to the promotion of porcine pre-adipocyte differentiation, whereas overexpression leads to alterations in lipid metabolism within adipocytes .…”

Section: Adipocyte Differentiationmentioning

confidence: 99%

The role of sex steroids in white adipose tissue adipocyte function

Newell-Fugate

2017

Reproduction

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Abstractwith the increasing knowledge that gender influences normal physiology, much biomedical research has begun to focus on the differential effects of sex on tissue function. Sexual dimorphism in mammals is due to the combined effects of both genetic and hormonal factors. Hormonal factors are mutable particularly in females in whom the estrous cycle dominates the hormonal milieu. Given the severity of the obesity epidemic and the fact that there are differences in the obesity rates in men and women, the role of sex in white adipose tissue function is being recognized as increasingly important. Although sex differences in white adipose tissue distribution are well established, the mechanisms affecting differential function of adipocytes within white adipose tissue in males and females remain largely understudied and poorly understood. One of the largest differences in the endocrine environment in males and females is the concentration of circulating androgens and estrogens. This review examines the effects of androgens and estrogens on lipolysis/lipogenesis, adipocyte differentiation, insulin sensitivity and adipokine production in adipocytes from white adipose tissue with a specific emphasis on the sexual dimorphism of adipocyte function in white adipose tissue during both health and disease.Reproduction (2017) 153 R133-R149

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“…An effective targeted therapy for these tumors is still not available (4). Lately, the orphan nuclear receptor ERRα emerged as a promising target for alternative treatment of breast carcinomas (5,6). Expression of ERRα in breast tumors correlates with an increased risk of recurrence, a poor prognosis of the patients (7), and high expression of the tyrosine kinase ErbB2 (Her2/neu; ref.…”

Section: Introductionmentioning

confidence: 99%

Estrogen-Related Receptor α Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma

Heck

Rom²,

Thewes

et al. 2009

Cancer Research

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The significance of the estrogen-related receptor α (ERRα) as prognostic marker for poor clinical outcome in breast carcinoma has recently been reported. Transcriptional activity of nuclear receptors such as ERRα depends on coregulatory proteins. Thus, we compared the expression of different receptors, coregulators, and target genes on RNA and protein level in identical primary breast tumor samples (n = 48). We found a positive correlation between the transcripts of ERRα and AIB1 (amplified in breast cancer-1), a coactivator overexpressed in breast cancers and associated with resistance to antihormone treatment. These data were confirmed on protein level, studying an independent patient collection (n = 257). Expression of the estrogen-regulated gene pS2 was associated with ERRα only in tumors, where estrogen receptor (ERα) expression was low or absent. In ERα high expressing tumors, no correlation of ERRα and pS2 was observed. AIB1 interacts directly with ERRα as shown by fluorescence-resonance energy transfer, mammalian two-hybrid, and coimmunoprecipitation assays with endogenous proteins. It enhances ERRα transcriptional activity in ERα-negative breast cancer cell lines as shown in functional reporter gene assays. Blocking ERRα with an inverse agonist abolished interaction and coactivation by AIB1. Recruitment of both proteins to ERRα target gene promoters further supports the significance of their interaction. Our findings identify AIB1 as functionally relevant cofactor for ERRα in breast carcinoma. ERRα/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner. Accordingly, ERRα might be a rewarding target for treatment of endocrine-resistant tumors. [Cancer Res 2009;69(12):5186-93]

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Estrogen-related receptor α as a therapeutic target in cancer

Cited by 102 publications

References 34 publications

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

The role of sex steroids in white adipose tissue adipocyte function

Estrogen-Related Receptor α Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma

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