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Donald P. Mcdonnell - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.
Cell reports, 2019Co-Authors: Sunghee Park, Ching-yi Chang, Rachid Safi, Xiaojing Liu, Robert Baldi, Wen Liu, Juan Liu, Jason W. Locasale, Donald P. McdonnellAbstract:Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of Estrogen-Related Receptor Alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.
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Molecular Pathways: The Metabolic Regulator Estrogen-Related Receptor α as a Therapeutic Target in Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Ching-yi Chang, Donald P. McdonnellAbstract:The Estrogen Related Receptor Alpha (ERRα) is an orphan member of the nuclear Receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator activated Receptor gamma coactivator-1 Alpha and beta (PGC-1α or PGC-1β). Under normal physiological conditions, and in responding to different environmental stimuli, the ERRα/PGC-1 complex is involved in regulating metabolic homeostasis under conditions of high energy demand in brown adipocytes, proliferating T-cells and in muscle. Interestingly, increased expression/activity of the ERRα/PGC-1 axis has also been shown to correlate with unfavorable clinical outcome in both breast and ovarian tumors. The observation that ERRα activity is manifest in all breast tumor sub-types with particularly high activity being evident in ERα-negative, HER2 positive and triple negative breast cancers has raised significant interest in targeting this Receptor for the treatment of those breast cancers where therapeutic options are limited.
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The Metabolic Regulator ERRα, a Downstream Target of HER2/IGF-1R, as a Therapeutic Target in Breast Cancer
Cancer cell, 2011Co-Authors: Ching-yi Chang, Dmitri Kazmin, Jeff S. Jasper, Rebecca Kunder, William J. Zuercher, Donald P. McdonnellAbstract:A genomic signature designed to assess the activity of the Estrogen-Related Receptor Alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated Receptor activity. Importantly, this signature also predicted the ability of an ERRα antagonist, XCT790, to inhibit proliferation in cellular models of breast cancer. Using a chemical genomic approach, it was determined that activation of the Her2/IGF-1R signaling pathways and subsequent C-MYC stabilization upregulate the expression of peroxisome proliferator-activated Receptor gamma coactivator-1 beta (PGC-1β), an obligate cofactor for ERRα activity. PGC-1β knockdown in breast cancer cells impaired ERRα signaling and reduced cell proliferation, implicating a functional role for PGC-1β/ERRα in the pathogenesis of breast cancers.
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Estrogen-Related Receptor Alpha induces the expression of vascular endothelial growth factor in breast cancer cells.
The Journal of Steroid Biochemistry and Molecular Biology, 2009Co-Authors: Rebecca A. Stein, Stephanie Gaillard, Donald P. McdonnellAbstract:Estrogen-Related Receptor Alpha (ERRα) is an orphan member of the nuclear Receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRα has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERRα a putative negative prognostic factor, but we have recently found that knock-down of its expression retards tumor growth in a xenograft model of this disease. The specific aspects of ERRα function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1α as a protein ligand to regulate ERRα activity, we analyzed the effects of this Receptor on gene expression in the ERα-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERRα target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERRα in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. The induction of VEGF results from the interaction of ERRα with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERRα-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERRα is expressed and provide validation for its use as a therapeutic target in cancer.
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Estrogen-Related Receptor α as a therapeutic target in cancer
Endocrine-related cancer, 2006Co-Authors: Rebecca A. Stein, Donald P. McdonnellAbstract:The orphan Receptor Estrogen-Related Receptor Alpha (ERR Alpha) is a member of the nuclear Receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen Receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERR Alpha as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERR Alpha action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.
Jo Kitawaki - One of the best experts on this subject based on the ideXlab platform.
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Estrogen-Related Receptor Alpha induces epithelial-mesenchymal transition through cancer-stromal interactions in endometrial cancer
Scientific reports, 2019Co-Authors: Kaori Yoriki, Taisuke Mori, Tetsuya Kokabu, Hiroshi Matsushima, Shiori Umemura, Yosuke Tarumi, Jo KitawakiAbstract:Estrogen-Related Receptor Alpha (ERRα), which shares structural similarities with estrogen Receptors, is associated with tumor progression in endometrial cancer, but little is known about the detailed underlying mechanism. We investigated whether ERRα, in cooperation with peroxisome proliferator-activated Receptor gamma coactivator 1-Alpha (PGC-1α), could participate in epithelial-mesenchymal transition (EMT) in endometrial cancer through cancer-stromal interactions. Two endometrial cancer cell lines, Ishikawa and HEC-1A, transfected with ERRα/PGC-1α expression plasmids or silenced for ERRα expression, were co-cultured with telomerase-transformed human endometrial stromal cells (T-HESCs). We found that EMT-associated factors including vimentin, Snail, and zinc finger E-box binding homeobox 1 were upregulated in cancer cells overexpressing ERRα/PGC-1α and that transforming growth factor-beta (TGF-β) was induced in T-HESCs in the same conditions. In contrast, ERRα knockdown suppressed EMT-associated factors in cancer cells and TGF-β in T-HESCs. ERRα/PGC-1α overexpression increased the expression of EMT-associated factors after TGF-β exposure; however, it decreased E-cadherin at protein level. ERRα knockdown suppressed EMT-associated factors in the presence of TGF-β, whereas E-cadherin remained unchanged. Matrigel invasion assays revealed that ERRα knockdown attenuated the stimulation of migration and invasion by TGF-β. These findings suggest that ERRα is a potential target for inhibiting TGF-β-induced EMT through cancer-stromal interactions in endometrial cancer.
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Anti-tumor effect of Estrogen-Related Receptor Alpha knockdown on uterine endometrial cancer
Oncotarget, 2016Co-Authors: Hiroshi Matsushima, Kaori Yoriki, Taisuke Mori, Tetsuya Kokabu, Shiori Umemura, Fumitake Ito, Takuro Yamamoto, Makoto Akiyama, Kyoko Akashi, Jo KitawakiAbstract:// Hiroshi Matsushima 1 , Taisuke Mori 1 , Fumitake Ito 1 , Takuro Yamamoto 1 , Makoto Akiyama 1 , Tetsuya Kokabu 1 , Kaori Yoriki 1 , Shiori Umemura 1 , Kyoko Akashi 1 and Jo Kitawaki 1 1 Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kajii-cho, Kamigyo-ku, Kyoto, Japan Correspondence to: Taisuke Mori, email: // Keywords : apoptosis, cell cycle arrest, ERRα, VEGF, uterine endometrial cancer Received : December 24, 2015 Accepted : April 16, 2016 Published : May 03, 2016 Abstract Estrogen-Related Receptor (ERR)α presents structural similarities with estrogen Receptor (ER)α. However, it is an orphan Receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type ( p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro ( p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts ( p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer.
Ching-yi Chang - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.
Cell reports, 2019Co-Authors: Sunghee Park, Ching-yi Chang, Rachid Safi, Xiaojing Liu, Robert Baldi, Wen Liu, Juan Liu, Jason W. Locasale, Donald P. McdonnellAbstract:Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of Estrogen-Related Receptor Alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.
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ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer.
Cell reports, 2016Co-Authors: Sunghee Park, Ching-yi Chang, Jeff S. Jasper, Rachid Safi, Xiaojing Liu, Robert Baldi, Grace R. Anderson, Tingyu Liu, Jeffrey C. Rathmell, Mark W. DewhirstAbstract:Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear Receptor, Estrogen-Related Receptor Alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.
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Molecular Pathways: The Metabolic Regulator Estrogen-Related Receptor α as a Therapeutic Target in Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Ching-yi Chang, Donald P. McdonnellAbstract:The Estrogen Related Receptor Alpha (ERRα) is an orphan member of the nuclear Receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator activated Receptor gamma coactivator-1 Alpha and beta (PGC-1α or PGC-1β). Under normal physiological conditions, and in responding to different environmental stimuli, the ERRα/PGC-1 complex is involved in regulating metabolic homeostasis under conditions of high energy demand in brown adipocytes, proliferating T-cells and in muscle. Interestingly, increased expression/activity of the ERRα/PGC-1 axis has also been shown to correlate with unfavorable clinical outcome in both breast and ovarian tumors. The observation that ERRα activity is manifest in all breast tumor sub-types with particularly high activity being evident in ERα-negative, HER2 positive and triple negative breast cancers has raised significant interest in targeting this Receptor for the treatment of those breast cancers where therapeutic options are limited.
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The Metabolic Regulator ERRα, a Downstream Target of HER2/IGF-1R, as a Therapeutic Target in Breast Cancer
Cancer cell, 2011Co-Authors: Ching-yi Chang, Dmitri Kazmin, Jeff S. Jasper, Rebecca Kunder, William J. Zuercher, Donald P. McdonnellAbstract:A genomic signature designed to assess the activity of the Estrogen-Related Receptor Alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated Receptor activity. Importantly, this signature also predicted the ability of an ERRα antagonist, XCT790, to inhibit proliferation in cellular models of breast cancer. Using a chemical genomic approach, it was determined that activation of the Her2/IGF-1R signaling pathways and subsequent C-MYC stabilization upregulate the expression of peroxisome proliferator-activated Receptor gamma coactivator-1 beta (PGC-1β), an obligate cofactor for ERRα activity. PGC-1β knockdown in breast cancer cells impaired ERRα signaling and reduced cell proliferation, implicating a functional role for PGC-1β/ERRα in the pathogenesis of breast cancers.
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Receptor-selective coactivators as tools to define the biology of specific Receptor-coactivator pairs.
Molecular cell, 2006Co-Authors: Stephanie Gaillard, Dmitri Kazmin, Linda L. Grasfeder, Christiane Haeffele, Edward K. Lobenhofer, Tzu Ming Chu, Russell D. Wolfinger, Timothy R. Koves, Deborah M. Muoio, Ching-yi ChangAbstract:In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear Receptors (ONRs). Indeed, it appears that many members of this Receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific Receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the Receptor interacting domain of each cofactor such that it interacts selectively with one nuclear Receptor. In this study, we describe the customization of PGC-1Alpha and its use to study the biology of the Estrogen-Related Receptor Alpha (ERRAlpha) in cultured liver cells.
Eriko Sato - One of the best experts on this subject based on the ideXlab platform.
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Sex steroids in uterine endometrial cancers.
Hormone molecular biology and clinical investigation, 2011Co-Authors: Jiro Fujimoto, Eriko SatoAbstract:Some uterine endometrial cancers conserve estrogen dependency in advancement. However, the concept of advancement in tumor is complicated, because it involves simple growth in primary tumor and secondary spreading. The expression manner of estrogen Receptor Alpha exon 5 splicing variant, ER beta, progesterone Receptor-A (N-terminus deletion mutant) is associated with metastatic potential in uterine endometrial cancers. Increased Estrogen-Related Receptor Alpha expression is related to tumor advancement with the loss of estrogen dependency. Steroid Receptor coactivator-3 contributes to tumor progression and can be used as a treatment target for advanced uterine endometrial cancers. Estrogen responsive oncogenes, c-jun and c-Ha-ras, are not modi-fied by progestin in uterine endometrial cancer cells and are considered to be an instinct phenotype as such cancers. By contrast, metastatic potential of estrogen-dependent uterine endometrial cancers can be partially controlled by progestin via metastasis-related genes, E-cadherin/catenins, plasminogen activator inhibitor-1, vascular endothelial growth factor. Thus, sex steroids related phenomena are impress-ive in the advancement of uterine endometrial cancers.
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Estrogenrelated Receptor in reproductive organs
Reproductive Medicine and Biology, 2005Co-Authors: Jiro Fujimoto, Yumiko Nakagawa, Hiroshi Toyqki, Hideki Sakaguchi, Eriko Sato, Teruhiko TamayaAbstract:Estrogen-Related Receptor (ERR) was studied in the placenta and uterine endometrium, especially endometrial cancers, among reproductive organs. In the placenta, the estrogen Receptor (ER) Alpha and beta mRNA levels increased from the first to the second trimester, and then decreased until normal term delivery. Estrogen-Related Receptor Alpha, beta and gamma mRNA levels gradually increased up to the second trimester, and then comparatively rapidly increased until normal term delivery. In endometrial cancers, ER Alpha and beta mRNA levels decreased with clinical stage, myometrial invasion and dedifferentiation. Estrogen-Related Receptor Alpha levels increased with clinical stage and myometrial invasion, and the ERR gamma levels increased with myometrial invasion. Estrogen-Related Receptors can bind to the steroid Receptor coactivator family without any ligands, and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show a competitive interaction associated with the use of common cofactors. It is speculated that the upregulation of ERR is related to the placental growth after the downregulation of ER from the second trimester until delivery, and that ERR Alpha and gamma are candidates for prognostic factors in endometrial cancer, although ERR are not directly related to tumor growth and advancement of endometrial cancer.
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Estrogen‐related Receptor in reproductive organs
Reproductive medicine and biology, 2005Co-Authors: Jiro Fujimoto, Yumiko Nakagawa, Hideki Sakaguchi, Eriko Sato, Hiroshi Toyoki, Teruhiko TamayaAbstract:Estrogen-Related Receptor (ERR) was studied in the placenta and uterine endometrium, especially endometrial cancers, among reproductive organs. In the placenta, the estrogen Receptor (ER) Alpha and beta mRNA levels increased from the first to the second trimester, and then decreased until normal term delivery. Estrogen-Related Receptor Alpha, beta and gamma mRNA levels gradually increased up to the second trimester, and then comparatively rapidly increased until normal term delivery. In endometrial cancers, ER Alpha and beta mRNA levels decreased with clinical stage, myometrial invasion and dedifferentiation. Estrogen-Related Receptor Alpha levels increased with clinical stage and myometrial invasion, and the ERR gamma levels increased with myometrial invasion. Estrogen-Related Receptors can bind to the steroid Receptor coactivator family without any ligands, and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show a competitive interaction associated with the use of common cofactors. It is speculated that the upregulation of ERR is related to the placental growth after the downregulation of ER from the second trimester until delivery, and that ERR Alpha and gamma are candidates for prognostic factors in endometrial cancer, although ERR are not directly related to tumor growth and advancement of endometrial cancer. (Reprod Med Biol 2005; 4: 129-131).
Felicity E B May - One of the best experts on this subject based on the ideXlab platform.
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Novel drugs that target the Estrogen-Related Receptor Alpha: Their therapeutic potential in breast cancer
Cancer Management and Research, 2014Co-Authors: Felicity E B MayAbstract:THE INCIDENCE OF BREAST CANCER CONTINUES TO RISE: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-Related Receptor Alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-Related Receptor Alpha is an orphan Receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-Related Receptor Alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen Receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen Receptor Alpha and Estrogen-Related Receptor Alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of Estrogen-Related Receptor Alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel drugs might have utility in the management of advanced breast cancer, and biomarkers for stratification of patients likely to benefit, are discussed. Finally, the potential side effects of the novel drugs on metabolism, osteoporosis, osteo-metastasis, and cachexia are considered.