Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

Sun, Pengming; Sehouli, Jalid; Denkert, Carsten; Mustea, Alexander; Könsgen, Dominique; Koch, Ines; Wei, Lihui; Lichtenegger, W.

doi:10.1007/s00109-005-0639-3

Cited by 124 publications

(130 citation statements)

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“…The association of ERR␣ expression in breast cancer with a poor clinical outcome suggests it plays a role in tumor progression and aggressiveness (43,44,46). Evidence of similar correlates that appear in cancers of the prostate (79), ovary (80), colon (81), and endometrium (82) continue to emerge. Because its function is generally constitutive, ERR␣ could potentially induce ER␣ target genes in hormonally responsive cancers in an estrogen-independent manner.…”

Section: Discussionmentioning

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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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: 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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“…33,34 It has been suggested that there is a key role of ERRs in the regulation of the estrogen signal pathway in tumors, though the mechanisms of this crosstalk are still unclear. 34,35 Ariazi et al 36 observed that an increased ERRg level was associated with preferred clinical outcomes; ERRg was overexpressed in 75% of breast cancer. A similar result found in ovarian cancer by Sun et al 35 suggested that ERRg seems to be a tumor marker for a favorable prognosis.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women

Sangrajrang

Sato²,

Sanada³

et al. 2009

Intl Journal of Cancer

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Estrogen and its metabolites are believed to play important roles in breast cancer, and its determinants include both genetic and lifestyle factors. The objective of the study is to investigate the association of breast cancer risk in Thailand with genetic polymorphisms in several genes involved in estrogen synthesis and metabolism. Five hundred and seventy patients with histopathologically confirmed breast cancer and 497 controls were included in the present study. Forty single nucleotide polymorphisms (SNPs) in the CYP1A1, CYP1A2, CYP1B1, CYP17, CYP19, CYP2C9, CYP2C19, AhR, ESR1, PGR, ERRG, COMT, HSD17B1, HSD17B2, EPHX1 and NQO1 genes were genotyped. Association of genotypes with breast cancer risk was evaluated using multivariate logistic regression, which suggested an altered risk for the following SNPs [gene, odds ratio (OR) . In addition, a stratified analysis by menopausal status indicated that the association of the CYP1A2 (rs762551) and CYP17 (rs743572) polymorphisms with breast cancer risk were mainly evident in premenopausal, while ERRG (rs1857407) was significant in postmenopausal women. These findings suggest that CYP1A2, CYP2C19, AhR, ERRG and CYP17 polymorphisms may play an important role in estrogen metabolism and modify individual susceptibility to breast cancer in Thai women. ' UICCKey words: breast cancer; estrogen metabolizing enzyme; single nucleotide polymorphisms Much of the variability in global breast cancer rates has been attributed to country-specific differences in the prevalence of risk factors that determine lifetime exposure to estrogen. Comparatively younger ages at menarche, older ages at first birth and/or menopause and a higher prevalence of postmenopausal obesity have been proposed as explanations for the disparate breast cancer incidence rates among American Caucasian (97/100,000) and Asian women (27/100,000).1,2 Cross cultural differences in height, diet, alcohol consumption and exogenous estrogen use are also believed to contribute to international differences, but to a lesser extent. 3,4 Age-specific breast cancer incidence also varies between high-and low-risk countries: the mean age at diagnosis in developing countries is lower than that for European and American populations.It can be hypothesized that estrogen metabolites contribute to the activation of the estrogen receptor and the generation of DNAdamaging molecular species. 5 The genes involved in the disposition of female sex hormones are well known, and include COMT (catechol-O-methyltransferase), HSD17B1 (17 b-hydroxysteroid dehydrogenase type 1), HSD17B2, ESR a (estrogen receptor a), PGR (progesterone receptor), ERRG (estrogen-related receptor g), NQO1 (NADPH quinine oxoreductase), EPHX1 (epoxide hydrolase), AhR (aryl hydrocarbon receptor a) and members of the cytochrome P450 family including CYP1A1, CYP1A2, CYP1B1, CYP17, CYP19, CYP2C9 and CYP2C19.Because Asian women have, on average, a 20% lower serum estradiol level than Western women, 6 it is possible that the effects of genetic polymorphisms of estrogen-...

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“…In addition, the receptor is essential for the regulation of mitochondrial biogenesis exerted by PGC-1␣ (23,24). ERR␣ is also expressed in a wide variety of tissues, and its high expression correlates with poor prognosis in breast, colon, and ovarian cancers (25)(26)(27)(28)(29). This suggests a role for ERR␣ in cell proliferation and/or invasion, which remains to be determined.…”

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confidence: 99%

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation

Bianco

Lanvin

Tribollet

et al. 2009

Journal of Biological Chemistry

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High expression of the estrogen receptor-related receptor (ERR)-␣ in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERR␣ reduces the proliferation of various cell lines and blocks the G 1 /S transition of the cell cycle in an ERR␣-dependent manner. XCT790 induces, in a p53-independent manner, the expression of the cell cycle inhibitor p21waf/cip1 at the protein, mRNA, and promoter level, leading to an accumulation of hypophosphorylated Rb. Finally, XCT790 reduces cell tumorigenicity in Nude mice.Breast cancer is the most common malignancy in women (1). In the initial phases, these tumors often depend on estrogens for their growth. At the molecular level, 17␤-estradiol (E2, 3 the main estrogen in the adult) acts by up-regulating the expression of cyclin D1, which regulates the activity of cyclin-dependent kinases (cdks) 4 and 6 (2, 3). These cdks facilitate the transition from the G 1 to the S phase of the cell cycle by hyperphosphorylating Rb (4). Adjuvant therapies aimed at counteracting the effects of estrogens are widely used (5). Anti-estrogens such as tamoxifen down-regulate the expression of cyclin D1 (3), whereas ICI182,780 (fulvestrant and faslodex) stimulates the expression of p21 waf/cip1 (hereafter referred to as p21) (6). This protein blocks the activity of the cyclin D-cdk complexes leading to hypophosphorylation of Rb and arrest in the G 1 phase of the cell cycle (4). However, a large proportion of breast cancers evolve so as to become resistant to anti-hormonal treatments through mechanisms that are not clearly characterized (1,5). This illustrates the need of new targets against which to develop innovative anti-cancer therapies.The effects of estrogens are mediated by two specific nuclear receptors (ER␣ and ER␤), which act as ligand-dependent transcription factors (7). Estrogen receptor-related receptors (ERR␣, -␤, and -␥) are other members of the nuclear receptor superfamily that share a high level of sequence identity with the ERs (8). However, no natural ligand has been identified for the ERRs, which are therefore considered as orphan receptors. Crystallographic studies have shown that ERR␣ and -␥ spontaneously adopt active conformations (9, 10). Although ERR␣ regulates transcription in a constitutive manner, some of its activities (DNA binding and contact with coactivators) can be regulated by phosphorylation (11). Furthermore, compounds such as the phytoestrogen genistein can inhibit the transcriptional activities of ERR␣ (12). In addition, based on its capacity to disrupt the interactions between ERR␣ and the PGC-1␣ coactivator, the synthetic molecule XCT790 has been identified as an ERR␣-specific inverse agonist (13). This compound down-regulates the expression of ERR␣ target genes probably by inducing an actively repressing conformation (14). At the same time, XCT790 promotes the proteasomedependent degradation of its receptor (15). ERR...

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Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

Cited by 124 publications

References 32 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

Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation

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