Estrogen-Related Receptor α in Human Breast Carcinoma as a Potent Prognostic Factor

Suzuki, Takashi; Miki, Yasuhiro; Moriya, Takuya; Shimada, Naoyuki; Ishida, Toru; Higuchi, Hisashi; Ohuchi, Noriaki; Sasano, Hironobu

doi:10.1158/0008-5472.can-04-0250

Cited by 209 publications

(225 citation statements)

References 49 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: 92%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…11), a marker of tumor aggressiveness. Suzuki et al (12) reported that f55% of human breast cancers are positive for ERRa by immunohistochemistry, with ERRapositive status being associated with greatly increased risk of recurrence and adverse clinical outcome. Thus, ERRa shows potential as a prognosticator and target for breast cancer therapy, with ERRa possibly playing an important role by substituting for ERa activities, especially in ErbB2-positive, ERa-negative, and tamoxifen-resistant tumors.…”

Section: Introductionmentioning

confidence: 99%

Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

Ariazi

Kraus

Farrell

et al. 2007

Molecular Cancer Research

105

106

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We previously showed that (a) estrogen-related receptor A1 (ERRA1) down-modulates estrogen receptor (ER) -stimulated transcription in low ErbB2 -expressing MCF-7 mammary carcinoma cells, and (b) ERRA and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRA1 represses ERA-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERRA1 activated estrogen response element -and ERR response element -mediated transcription in ERA-positive, high ErbB2 -expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERRA1 reflected the cell type -specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERRA1. Two-dimensional PAGE of radiophosphate-labeled ERRA1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERRA1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRA1 in vitro. ERRA1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/ Akt, with U0126 or LY294002, respectively. Thus, ERRA1 activities are regulated, in part, via ErbB2 signaling, with ERRA1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRA1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal-and ErbB2-based treatment options, with ERRA1 serving as a novel target for drug development. (Mol Cancer Res 2007;5(1):71 -85)

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“…[15][16][17][18] Further, ERRa is now established to be associated with unfavorable biomarkers in human breast cancer. [19][20][21] Much less is known, however, about the extent or pattern of ERRa expression in the prostate. 22 The present study evaluated ERRa expression in human prostate tissues and PC cell lines by immunohistochemistry and Western blot analysis to assess its clinical significance.…”

mentioning

confidence: 99%

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Fujimura

Takahashi

Urano

et al. 2007

Intl Journal of Cancer

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The nuclear receptor ERRα (estrogen‐related receptor α) is known to modulate the estrogen‐signaling pathway, but the biological significance of ERRα in the prostate remains unclear. We investigated the expression of ERRα in human prostate tissues and cancer cell lines to evaluate the potential roles of the receptor in prostate cancer (PC). Western blot analysis of ERRα was performed in three cell lines of human PC (LNCaP, DU145 and PC‐3). The expressions of ERRα in cancerous lesions (n = 106) and benign foci (n = 99) of 106 surgically obtained prostate specimens were evaluated by immunohistochemistry. The relationships between the ERRα expression and clinicopathological features were evaluated. Western blot analysis using the polyclonal anti‐ERRα antibody detected a 52 kD band in all three PC cell lines. Positive immunostaining of ERRα in the nuclei was found in 73 (69%) cancerous and 47 (47.5%) benign epithelium, whereas the stromal tissues were negative for ERRα. The mean immunoreactivity score (IR score) of the cancerous lesions (3.5 ± 2.6) was significantly higher than that of the benign foci (1.8 ± 2.1) (p < 0.0001). The IR score of the cancerous lesions significantly correlated with the Gleason score (p = 0.0135). Univariate and multivariate hazard analyses revealed significant correlations between elevated ERRα expression and poor cancer‐specific survival (p = 0.0141 and 0.0367, respectively). The enhanced expression of ERRα might play a role in the development of human PC and serve as a significant prognostic factor for the disease. © 2006 Wiley‐Liss, Inc.

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Estrogen-Related Receptor α in Human Breast Carcinoma as a Potent Prognostic Factor

Cited by 209 publications

References 49 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

Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

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