Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

ERRα: unraveling its role as a key player in cell migration

Oncogene volume 43, pages 379–387 (2024)Cite this article

Subjects

Abstract

Cell migration is essential throughout the life of multicellular organisms, and largely depends on the spatial and temporal regulation of cytoskeletal dynamics, cell adhesion and signal transduction. Interestingly, Estrogen-related receptor alpha (ERRα) has been identified as a major regulator of cell migration in both physiological and pathological conditions. ERRα is an orphan member of the nuclear hormone receptor superfamily of transcription factors and displays many biological functions. ERRα is a global regulator of energy metabolism, and it is also highly involved in bone homeostasis, development, differentiation, immunity and cancer progression. Importantly, in some instances, the regulation of these biological processes relies on the ability to orchestrate cell movements. Therefore, this review describes how ERRα-mediated cell migration contributes not only to tissue homeostasis but also to tumorigenesis and metastasis, and highlights the molecular and cellular mechanisms by which ERRα finely controls the cell migratory potential.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Core mechanisms of cell migration.
Fig. 2: ERRα regulates cell migration in both physiological and pathological conditions.
Fig. 3: Molecular mechanisms through which ERRα finely controls migration potential.

Similar content being viewed by others

References

  1. Mayor R, Etienne-Manneville S. The front and rear of collective cell migration. Nat Rev Mol Cell Biol. 2016;17:97–109.

    Article  CAS  PubMed  Google Scholar 

  2. Bravo-Cordero JJ, Hodgson L, Condeelis J. Directed cell invasion and migration during metastasis. Curr Opin Cell Biol. 2012;24:277–83.

    Article  CAS  PubMed  Google Scholar 

  3. De Pascalis C, Etienne-Manneville S. Single and collective cell migration: the mechanics of adhesions. Mol Biol Cell. 2017;28:1833–46.

    Article  PubMed  PubMed Central  Google Scholar 

  4. SenGupta S, Parent CA, Bear JE. The principles of directed cell migration. Nat Rev Mol Cell Biol. 2021;22:529–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gardel ML, Schneider IC, Aratyn-Schaus Y, Waterman CM. Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev Cell Dev Biol. 2010;26:315–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018;217:447–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Seetharaman S, Etienne-Manneville S. Cytoskeletal crosstalk in cell migration. Trends Cell Biol. 2020;30:720–35.

    Article  CAS  PubMed  Google Scholar 

  8. Villena JA, Kralli A. ERRα: a metabolic function for the oldest orphan. Trends Endocrinol Metab. 2008;19:269–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tam IS, Giguère V. There and back again: the journey of the estrogen-related receptors in the cancer realm. J Steroid Biochem Mol Biol. 2016;157:13–19.

    Article  CAS  PubMed  Google Scholar 

  10. Ranhotra HS. The estrogen-related receptors in metabolism and cancer: newer insights. J Receptors Signal Transduct. 2018;38:95–100.

    Article  CAS  Google Scholar 

  11. Giguère V, Yang N, Segui P, Evans RM. Identification of a new class of steroid hormone receptors. Nature. 1988;331:91–94.

    Article  PubMed  ADS  Google Scholar 

  12. Crevet L, Vanacker J-M. Regulation of the expression of the estrogen related receptors (ERRs). Cell Mol Life Sci. 2020;77:4573–9.

    Article  CAS  PubMed  Google Scholar 

  13. Tripathi M, Yen PM, Singh BK. Estrogen-related receptor alpha: an under-appreciated potential target for the treatment of metabolic diseases. IJMS. 2020;21:1645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol. 2013;5:a016709–a016709.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huss JM, Garbacz WG, Xie W. Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim. Biophys. Acta (BBA) Mol Basis Dis. 2015;1852:1912–27.

    Article  CAS  Google Scholar 

  16. Sladek R, Bader JA, Giguère V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol. 1997;17:5400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vanacker J-M. Transcriptional activities of the orphan nuclear receptor ERR (Estrogen Receptor-Related Receptor-). Mol Endocrinol. 1999;13:764–73.

    CAS  PubMed  Google Scholar 

  18. Mohideen-Abdul K, Tazibt K, Bourguet M, Hazemann I, Lebars I, Takacs M, et al. Importance of the sequence-directed DNA shape for specific binding site recognition by the estrogen-related receptor. Front Endocrinol. 2017;8:140.

    Article  Google Scholar 

  19. Patel AKM, Vilela P, Shaik TB, McEwen AG, Hazemann I, Brillet K, et al. Asymmetric dimerization in a transcription factor superfamily is promoted by allosteric interactions with DNA. Nucleic Acids Res. 2023;51:8864–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kallen J, Schlaeppi J-M, Bitsch F, Filipuzzi I, Schilb A, Riou V, et al. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor α (ERRα). J Biol Chem. 2004;279:49330–7.

    Article  CAS  PubMed  Google Scholar 

  21. Bianco S, Sailland J, Vanacker J-M. ERRs and cancers: Effects on metabolism and on proliferation and migration capacities. J Steroid Biochem Mol Biol. 2012;130:180–5.

    Article  CAS  PubMed  Google Scholar 

  22. Deblois G, Giguère V. Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease. Biochim Biophys Acta (BBA) Mol Basis Dis. 2011;1812:1032–40.

    Article  CAS  Google Scholar 

  23. Ariazi EA, Kraus RJ, Farrell ML, Jordan VC, Mertz JE. Estrogen-related receptor 1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway. Mol Cancer Res. 2007;5:71–85.

    Article  CAS  PubMed  Google Scholar 

  24. Barry JB, Giguere V. Epidermal growth factor–induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor A. Cancer Res. 2005;65:6120–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tremblay AM, Wilson BJ, Yang X-J, Giguère V. Phosphorylation-dependent sumoylation regulates estrogen-related Receptor-α and -γ transcriptional activity through a synergy control motif. Mol Endocrinol. 2008;22:570–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vu EH, Kraus RJ, Mertz JE. Phosphorylation-dependent sumoylation of estrogen-related receptor α1. Biochemistry. 2007;46:9795–804.

    Article  CAS  PubMed  Google Scholar 

  27. Wilson BJ, Tremblay AM, Deblois G, Sylvain-Drolet G, Giguère V. An acetylation switch modulates the transcriptional activity of estrogen-related receptor α. Mol Endocrinol. 2010;24:1349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Audet-walsh É, Giguére V. The multiple universes of estrogen-related receptor α and γ in metabolic control and related diseases. Acta Pharmacol Sin. 2015;36:51–61.

    Article  CAS  PubMed  Google Scholar 

  29. Alaynick WA, Kondo RP, Xie W, He W, Dufour CR, Downes M, et al. ERRγ directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 2007;6:13–24.

    Article  CAS  PubMed  Google Scholar 

  30. Dufour CR, Wilson BJ, Huss JM, Kelly DP, Alaynick WA, Downes M, et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ. Cell Metab. 2007;5:345–56.

    Article  CAS  PubMed  Google Scholar 

  31. Carnesecchi J, Vanacker J-M. Estrogen-related receptors and the control of bone cell fate. Mol Cell Endocrinol. 2016;432:37–43.

    Article  CAS  PubMed  Google Scholar 

  32. Guo X, Yue L, Li M, Dai A, Sun J, Fang L, et al. Nuclear receptor estrogen-related receptor gamma suppresses colorectal cancer aggressiveness by regulating Wnt/β-catenin signaling. Carcinogenesis. 2022;43:865–73.

    Article  CAS  PubMed  Google Scholar 

  33. Gulwani D, Upadhyay P, Goel R, Sarangthem V, Debraj Singh T. Unfolding of imminent bio-signatures in the prognosis of thyroid cancer; the emergence of estrogen related receptor gamma (ERRγ) as a hurricane. Asian Pac J Cancer Prev. 2023;24:375–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tiraby C, Hazen BC, Gantner ML, Kralli A. Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth. Cancer Res. 2011;71:2518–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kang M-H, Choi H, Oshima M, Cheong J-H, Kim S, Lee JH, et al. Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer. Nat Commun. 2018;9:1920.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  36. Riggins RB, Lan JP-J, Zhu Y, Klimach U, Zwart A, Cavalli LR, et al. ERRγ mediates Tamoxifen resistance in novel models of invasive lobular breast cancer. Cancer Res. 2008;68:8908–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K, Fujimura T, Tsuda H, et al. Estrogen-related receptor γ modulates cell proliferation and estrogen signaling in breast cancer. J Steroid Biochem Mol Biol. 2011;123:1–7.

    Article  CAS  PubMed  Google Scholar 

  38. Heckler MM, Thakor H, Schafer CC, Riggins RB. ERK/MAPK regulates ERRγ expression, transcriptional activity, and receptor-mediated Tamoxifen resistance in ER+ breast cancer. FEBS J. 2014;281:2431–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim J-H, Choi Y-K, Byun J-K, Kim M-K, Kang YN, Kim SH, et al. Estrogen-related receptor γ is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of p21 and p27. Exp Mol Med. 2016;48:e213–e213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hua T, Wang X, Chi S, Liu Y, Feng D, Zhao Y, et al. Estrogen‑related receptor γ promotes the migration and metastasis of endometrial cancer cells by targeting S100A4. Oncol Rep. 2018;40:823–32.

    Article  CAS  PubMed  Google Scholar 

  41. Zhou W, Liu Z, Wu J, Liu J, Hyder SM, Antoniou E, et al. Identification and characterization of two novel splicing isoforms of human estrogen-related receptor β. J Clin Endocrinol Metab. 2006;91:569–79.

    Article  CAS  PubMed  Google Scholar 

  42. Tiek DM, Khatib SA, Trepicchio CJ, Heckler MM, Divekar SD, Sarkaria JN, et al. Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. FASEB J. 2019;33:13476–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Heckler MM, Zeleke TZ, Divekar SD, Fernandez AI, Tiek DM, Woodrick J, et al. Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer. Oncotarget. 2016;7:47201–20.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ranhotra HS. Estrogen-related receptor alpha in select host functions and cancer: new frontiers. Mol Cell Biochem. 2022;477:1349–59.

    Article  CAS  PubMed  Google Scholar 

  45. Huss JM, Kopp RP, Kelly DP. Peroxisome Proliferator-activated Receptor Coactivator-1α (PGC-1α) Coactivates the Cardiac-enriched Nuclear Receptors Estrogen-related Receptor-α and -γ. J Biol Chem. 2002;277:40265–74.

    Article  CAS  PubMed  Google Scholar 

  46. Schreiber SN, Knutti D, Brogli K, Uhlmann T, Kralli A. The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor α (ERRα). J Biol Chem. 2003;278:9013–8.

    Article  CAS  PubMed  Google Scholar 

  47. Deblois G, Giguère V. Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer. 2013;13:27–36.

    Article  CAS  PubMed  Google Scholar 

  48. Vanacker J-M, Bonnelye E, Delmarre C, Laudet V. Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα. Oncogene. 1998;17:2429–35.

    Article  CAS  PubMed  Google Scholar 

  49. Singh BK, Sinha RA, Tripathi M, Mendoza A, Ohba K, Sy JAC, et al. Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci Signal. 2018;11:eaam5855.

    Article  PubMed  Google Scholar 

  50. Flamini MI, Uzair ID, Pennacchio GE, Neira FJ, Mondaca JM, Cuello-Carrión FD, et al. Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases. Horm Cancer. 2017;8:16–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Uzair ID, Conte Grand J, Flamini MI, Sanchez AM. Molecular actions of thyroid hormone on breast cancer cell migration and invasion via cortactin/N-WASP. Front Endocrinol. 2019;10:139.

    Article  Google Scholar 

  52. Bonnelye E, Vanacker JM, Spruyt N, Alric S, Fournier B, Desbiens X, et al. Expression of the estrogen-related receptor 1 (ERR-1) orphan receptor during mouse development. Mech Dev. 1997;65:71–85.

    Article  CAS  PubMed  Google Scholar 

  53. Huss JM, Torra IP, Staels B, Giguère V, Kelly DP. Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol. 2004;24:9079–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Murray J, Huss JM. Estrogen-related receptor α regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway. Am J Physiol Cell Physiol. 2011;301:C630–C645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shao D, Liu Y, Liu X, Zhu L, Cui Y, Cui A, et al. PGC-1β-Regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERRα. Mitochondrion. 2010;10:516–27.

    Article  CAS  PubMed  Google Scholar 

  56. Wei W, Schwaid AG, Wang X, Wang X, Chen S, Chu Q, et al. Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects. Cell Metab. 2016;23:479–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. LaBarge S, McDonald M, Smith-Powell L, Auwerx J, Huss JM. Estrogen-related receptor-α (ERRα) deficiency in skeletal muscle impairs regeneration in response to injury. FASEB J. 2014;28:1082–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Delhon I, Gutzwiller S, Morvan F, Rangwala S, Wyder L, Evans G, et al. Absence of estrogen receptor-related-α increases osteoblastic differentiation and cancellous bone mineral density. Endocrinology. 2009;150:4463–72.

    Article  CAS  PubMed  Google Scholar 

  59. Teyssier C, Gallet M, Rabier B, Monfoulet L, Dine J, Macari C, et al. Absence of ERRα in female mice confers resistance to bone loss induced by age or estrogen-deficiency. PLoS ONE. 2009;4:e7942.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  60. Gallet M, Saïdi S, Haÿ E, Photsavang J, Marty C, Sailland J, et al. Repression of osteoblast maturation by ERRα accounts for bone loss induced by estrogen deficiency. PLoS ONE. 2013;8:e54837.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  61. Bonnelye E, Zirngibl RA, Jurdic P, Aubin JE. The orphan nuclear estrogen receptor-related receptor-α regulates cartilage formation in vitro: implication of Sox9. Endocrinology. 2007;148:1195–205.

    Article  CAS  PubMed  Google Scholar 

  62. Rajalin A-M, Pollock H, Aarnisalo P. ERRα regulates osteoblastic and adipogenic differentiation of mouse bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 2010;396:477–82.

    Article  CAS  PubMed  Google Scholar 

  63. Ariazi EA, Clark GM, Mertz JE. Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human. Breast Cancer. 2002;62:6510–8.

    CAS  Google Scholar 

  64. Suzuki T, Miki Y, Moriya T, Shimada N, Ishida T, Hirakawa H, et al. Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor. Cancer Res. 2004;64:4670–6.

    Article  CAS  PubMed  Google Scholar 

  65. Cavallini A, Notarnicola M, Giannini R, Montemurro S, Lorusso D, Visconti A, et al. Oestrogen receptor-related receptor alpha (ERRα) and oestrogen receptors (ERα and ERβ) exhibit different gene expression in human colorectal tumour progression. Eur J Cancer. 2005;41:1487–94.

    Article  CAS  PubMed  Google Scholar 

  66. Sun P, Sehouli J, Denkert C, Mustea A, Könsgen D, Koch I, et al. Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells. J Mol Med. 2005;83:457–67.

    Article  CAS  PubMed  Google Scholar 

  67. Cheung CP, Yu S, Wong KB, Chan LW, Lai FMM, Wang X, et al. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. J Clin Endocrinol Metab. 2005;90:1830–44.

    Article  CAS  PubMed  Google Scholar 

  68. Fujimura T, Takahashi S, Urano T, Kumagai J, Ogushi T, Horie‐Inoue K, et al. Increased expression of estrogen-related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer. Int J Cancer. 2007;120:2325–30.

    Article  CAS  PubMed  Google Scholar 

  69. Fujimoto J, Alam SM, Jahan I, Sato E, Sakaguchi H, Tamaya T. Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers. J Steroid Biochem Mol Biol. 2007;104:301–4.

    Article  CAS  PubMed  Google Scholar 

  70. Fujimoto J, Sato E. Clinical implication of estrogen-related receptor (ERR) expression in uterine endometrial cancers. J Steroid Biochem Mol Biol. 2009;116:71–75.

    Article  CAS  PubMed  Google Scholar 

  71. Tiwari A, Swamy S, Gopinath KS, Kumar A. Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo. Sci Rep. 2015;5:17621.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  72. Li P, Wang J, Wu D, Ren X, Wu W, Zuo R, et al. ERRα is an aggressive factor in lung adenocarcinoma indicating poor prognostic outcomes. Cancer Manag Res. 2019;11:8111–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu S-L, Wu X-S, Li F-N, Yao W-Y, Wu Z-Y, Dong P, et al. ERRα promotes pancreatic cancer progression by enhancing the transcription of PAI1 and activating the MEK/ERK pathway. Am J Cancer Res. 2020;10:3622–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bernatchez G, Giroux V, Lassalle T, Carpentier AC, Rivard N, Carrier JC. ERRα metabolic nuclear receptor controls growth of colon cancer cells. Carcinogenesis. 2013;34:2253–61.

    Article  CAS  PubMed  Google Scholar 

  75. Bianco S, Lanvin O, Tribollet V, Macari C, North S, Vanacker J-M. Modulating estrogen receptor-related receptor-alpha activity inhibits cell proliferation. J Biol Chem. 2009;284:23286–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhao Y, Li Y, Lou G, Zhao L, Xu Z, Zhang Y, et al. MiR-137 targets estrogen-related receptor alpha and impairs the proliferative and migratory capacity of breast cancer cells. PLoS ONE. 2012;7:e39102.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  77. Mukherjee T, Malik P, Hoidal J. The emerging role of estrogen related receptorα in complications of non‑small cell lung cancers (Review). Oncol Lett. 2021;21:258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stein RA, Gaillard S, McDonnell DP. Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells. J Steroid Biochem Mol Biol. 2009;114:106–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang K, Lu J, Mori T, Smith-Powell L, Synold TW, Chen S, et al. Baicalin increases VEGF expression and angiogenesis by activating the ERR{alpha}/PGC-1{alpha} pathway. Cardiovasc Res. 2011;89:426–35.

    Article  CAS  PubMed  Google Scholar 

  80. Zou C, Yu S, Xu Z, Wu D, Ng C-F, Yao X, et al. ERRα augments HIF-1 signalling by directly interacting with HIF-1α in normoxic and hypoxic prostate cancer cells. J Pathol. 2014;233:61–73.

    Article  CAS  PubMed  Google Scholar 

  81. Ao A, Wang H, Kamarajugadda S, Lu J. Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci USA. 2008;105:7821–6.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  82. Tennessen JM, Baker KD, Lam G, Evans J, Thummel CS. The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab. 2011;13:139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cai Q, Lin T, Kamarajugadda S, Lu J. Regulation of glycolysis and the Warburg effect by estrogen-related receptors. Oncogene. 2013;32:2079–86.

    Article  CAS  PubMed  Google Scholar 

  84. Sailland J, Tribollet V, Forcet C, Billon C, Barenton B, Carnesecchi J, et al. Estrogen-related receptor α decreases RHOA stability to induce orientated cell migration. Proc Natl Acad Sci USA. 2014;111:15108–13.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  85. Carnesecchi J, Forcet C, Zhang L, Tribollet V, Barenton B, Boudra R, et al. ERRα induces H3K9 demethylation by LSD1 to promote cell invasion. Proc Natl Acad Sci USA. 2017;114:3909–14.

    Article  MathSciNet  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  86. Zhang L, Carnesecchi J, Cerutti C, Tribollet V, Périan S, Forcet C, et al. LSD1-ERRα complex requires NRF1 to positively regulate transcription and cell invasion. Sci Rep. 2018;8:10041.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  87. Weng S, Wallingford JB. May the force be with you. eLife. 2018;7:e36662.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Bardet P-L, Horard B, Laudet V, Vanacker J-M. The ERRα orphan nuclear receptor controls morphogenetic movements during zebrafish gastrulation. Dev Biol. 2005;281:102–11.

    Article  CAS  PubMed  Google Scholar 

  89. Ulrich F, Concha ML, Heid PJ, Voss E, Witzel S, Roehl H, et al. Slb/Wnt11 controls hypoblast cell migration and morphogenesis at the onset of zebrafish gastrulation. Development. 2003;130:5375–84.

    Article  CAS  PubMed  Google Scholar 

  90. Dwyer MA, Joseph J, Wade HE, Eaton ML, Kunder RS, Kazmin D, et al. WNT11 expression is induced by ERRα and β-catenin and acts in an autocrine manner to increase cancer cell migration. Cancer Res. 2010;70:9298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bonnelye E, Saltel F, Chabadel A, Zirngibl RA, Aubin JE, Jurdic P. Involvement of the orphan nuclear estrogen receptor-related receptor α in osteoclast adhesion and transmigration. J Mol Endocrinol. 2010;45:365–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Likhite N, Yadav V, Milliman EJ, Sopariwala DH, Lorca S, Narayana NP, et al. Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial Cells. Mol Cell Biol. 2019;39:e00411–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Arany Z, Foo S-Y, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature. 2008;451:1008–12.

    Article  CAS  PubMed  ADS  Google Scholar 

  94. Fradet A, Sorel H, Bouazza L, Goehrig D, Depalle B, Bellahcene A, et al. Dual function of ERR in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin. Cancer Res. 2011;71:5728–38.

    Article  CAS  PubMed  Google Scholar 

  95. Zhang L-D, Chen L, Zhang M, Qi H-J, Chen L, Chen H-F, et al. Downregulation of ERRα inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signaling pathway. Eur J Pharmacol. 2015;769:167–76.

    Article  CAS  PubMed  Google Scholar 

  96. Benslimane-Ahmim Z, Pereira J, Lokajczyk A, Dizier B, Galy-Fauroux I, Fischer A-M, et al. Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization. Cancer Lett. 2017;395:11–19.

    Article  CAS  PubMed  Google Scholar 

  97. Sumi D, Ignarro LJ. Estrogen-related receptor 1 up-regulates endothelial nitric oxide synthase expression. Proc Natl Acad Sci USA. 2003;100:14451–6.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  98. Xia W, Yin J, Zhang S, Guo C, Li Y, Zhang Y, et al. Parkin modulates ERRα/eNOS signaling pathway in endothelial cells. Cell Physiol Biochem. 2018;49:2022–34.

    Article  CAS  PubMed  Google Scholar 

  99. Hu W, Huang Y. Targeting the platelet-derived growth factor signalling in cardiovascular disease. Clin Exp Pharmacol Physiol. 2015;42:1221–4.

    Article  CAS  PubMed  Google Scholar 

  100. Li Q, Zhu L, Zhang L, Chen H, Zhu Y, Du Y, et al. Inhibition of estrogen related receptor α attenuates vascular smooth muscle cell proliferation and migration by regulating RhoA/p27 Kip1 and β-Catenin/Wnt4 signaling pathway. Eur J Pharmacol. 2017;799:188–95.

    Article  CAS  PubMed  Google Scholar 

  101. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Huang J, Guan B, Yin L, Liu F, Hu B, Zheng Q, et al. Effects of estrogen-related receptor alpha (ERRα) on proliferation and metastasis of human lung cancer A549 cells. J Huazhong Univ Sci Technol [Med Sci]. 2014;34:875–81.

    Article  CAS  Google Scholar 

  103. Wu Y-M, Chen Z-J, Liu H, Wei W-D, Lu L-L, Yang X-L, et al. Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin. Oncotarget. 2015;6:25588–601.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chen H, Pan J, Zhang L, Chen L, Qi H, Zhong M, et al. Downregulation of estrogen-related receptor alpha inhibits human cutaneous squamous cell carcinoma cell proliferation and migration by regulating EMT via fibronectin and STAT3 signaling pathways. Eur J Pharmacol. 2018;825:133–42.

    Article  CAS  PubMed  Google Scholar 

  105. Yoriki K, Mori T, Kokabu T, Matsushima H, Umemura S, Tarumi Y, et al. Estrogen-related receptor alpha induces epithelial-mesenchymal transition through cancer-stromal interactions in endometrial cancer. Sci Rep. 2019;9:6697.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  106. Wang L, Yang M, Guo X, Yang Z, Liu S, Ji Y, et al. Estrogen‐related receptor‐α promotes gallbladder cancer development by enhancing the transcription of Nectin‐4. Cancer Sci. 2020;111:1514–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mao X, Lei H, Yi T, Su P, Tang S, Tong Y, et al. Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression. J Exp Clin Cancer Res. 2022;41:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Li F-N, Zhang Q-Y, Li O, Liu S-L, Yang Z-Y, Pan L-J, et al. ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1. Int J Biol Sci. 2021;17:1909–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lam SS, Mak AS, Yam JW, Cheung AN, Ngan HY, Wong AS. Targeting estrogen-related receptor alpha inhibits epithelial-to-mesenchymal transition and stem cell properties of ovarian cancer Cells. Mol Ther. 2014;22:743–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ma J-H, Qi J, Lin S-Q, Zhang C-Y, Liu F, Xie W-D, et al. STAT3 targets ERR-α to promote epithelial–mesenchymal transition, migration, and invasion in triple-negative breast cancer cells. Mol Cancer Res. 2019;17:2184–95.

    Article  CAS  PubMed  Google Scholar 

  111. Chen Y, Zhang K, Li Y, He Q. Estrogen-related receptor α participates transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition of osteosarcoma cells. Cell Adh Migr. 2016;11:338–46.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Huang X, Wang X, Shang J, Zhaang Z, Cui B, Lin Y, et al. Estrogen related receptor alpha triggers the migration and invasion of endometrial cancer cells via up regulation of TGFB1. Cell Adh Migr. 2018;12:538–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Luo J, Sladek R, Carrier J, Bader J-A, Richard D, Giguere V. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol. 2003;23:7947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A. Orphan nuclear receptor estrogen-related receptor α is essential for adaptive thermogenesis. Proc Natl Acad Sci USA. 2007;104:1418–23.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  115. Cui H, Lu Y, Khan MZ, Anderson RM, McDaniel L, Wilson HE, et al. Behavioral disturbances in estrogen-related receptor alpha-null mice. Cell Rep. 2015;11:344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. De Jesús-Cortés H, Lu Y, Anderson RM, Khan MZ, Nath V, McDaniel L, et al. Loss of estrogen-related receptor alpha disrupts ventral-striatal synaptic function in female mice. Neuroscience. 2016;329:66–73.

    Article  PubMed  Google Scholar 

  117. Stein RA, Chang C, Kazmin DA, Way J, Schroeder T, Wergin M, et al. Estrogen-related receptor α is critical for the growth of estrogen receptor–negative breast cancer. Cancer Res. 2008;68:8805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Deblois G, Hall JA, Perry M-C, Laganiere J, Ghahremani M, Park M, et al. Genome-wide identification of direct target genes implicates estrogen-related receptor as a determinant of breast cancer heterogeneity. Cancer Res. 2009;69:6149–57.

    Article  CAS  PubMed  Google Scholar 

  119. Deblois G, Chahrour G, Perry M-C, Sylvain-Drolet G, Muller WJ, Giguère V. Transcriptional control of the ERBB2 amplicon by ERRα and PGC-1β promotes mammary gland tumorigenesis. Cancer Res. 2010;70:10277–87.

    Article  CAS  PubMed  Google Scholar 

  120. Yu G, Lin J, Liu C, Hou K, Liang M, Shi B. Long non-coding RNA SPRY4-IT1 promotes development of hepatic cellular carcinoma by interacting with ERRα and predicts poor prognosis. Sci Rep. 2017;7. https://doi.org/10.1038/s41598-017-16781-9.

  121. Avena P, De Luca A, Chimento A, Nocito MC, Sculco S, La Padula D, et al. Estrogen related receptor alpha (ERRα) a bridge between metabolism and adrenocortical cancer progression. Cancers. 2022;14:3885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cerutti C, Zhang L, Tribollet V, Shi J-R, Brillet R, Gillet B, et al. Computational identification of new potential transcriptional partners of ERRα in breast cancer cells: specific partners for specific targets. Sci Rep. 2022;12:3826.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  123. Cerutti C, Shi J-R, Vanacker J-M. Multifaceted transcriptional network of estrogen-related receptor alpha in health and disease. Int J Mol Sci. 2023;24:4265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Auld KL, Berasi SP, Liu Y, Cain M, Zhang Y, Huard C, et al. Estrogen-related receptor α regulates osteoblast differentiation via Wnt/β-catenin signaling. J Mol Endocrinol. 2012;48:177–91.

    Article  CAS  PubMed  Google Scholar 

  125. Berman AY, Manna S, Schwartz NS, Katz YE, Sun Y, Behrmann CA, et al. ERRα regulates the growth of triple-negative breast cancer cells via S6K1-dependent mechanism. Sig Transduct Target Ther. 2017;2:17035.

    Article  Google Scholar 

  126. Chaveroux C, Eichner LJ, Dufour CR, Shatnawi A, Khoutorsky A, Bourque G, et al. Molecular and genetic crosstalks between mTOR and ERRα Are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab. 2013;17:586–98.

    Article  CAS  PubMed  Google Scholar 

  127. Torrano V, Valcarcel-Jimenez L, Cortazar AR, Liu X, Urosevic J, Castillo-Martin M, et al. The metabolic co-regulator PGC1α suppresses prostate cancer metastasis. Nat Cell Biol. 2016;18:645–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Valcarcel-Jimenez L, Macchia A, Crosas-Molist E, Schaub-Clerigué A, Camacho L, Martín-Martín N, et al. PGC1α suppresses prostate cancer cell invasion through ERRα transcriptional control. Cancer Res. 2019;79:6153–65.

    Article  CAS  PubMed  Google Scholar 

  129. Vargas G, Bouchet M, Bouazza L, Reboul P, Boyault C, Gervais M, et al. ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. Oncogene. 2019;38:950–64.

    Article  CAS  PubMed  Google Scholar 

  130. Tribollet V, Barenton B, Kroiss A, Vincent S, Zhang L, Forcet C, et al. miR-135a inhibits the invasion of cancer cells via suppression of ERRα. PLoS ONE. 2016;11:e0156445.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Han L, Liu B, Jiang L, Liu J, Han S. MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha. Tumor Biol. 2016;37:13205–14.

    Article  CAS  Google Scholar 

  132. Tribollet V, Cerutti C, Géloën A, Berger E, De Mets R, Balland M, et al. ERRα coordinates actin and focal adhesion dynamics. Cancer Gene Ther. 2022;29:1429–38.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in our laboratories is funded by Ligue contre le Cancer (comités Rhône, Ardèche and Drôme), ANSES (Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail, grant EST15-076), JoRiss/ENS research program and Région Auvergne-Rhône-Alpes (grant SCUSI OPE2017_004). The authors thank Violaine Tribollet for helpful discussions.

Author information

Authors and Affiliations

  1. Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Lyon, France

    Jean-Marc Vanacker

  2. Institut de Génomique Fonctionnelle de Lyon, UMR5242, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard-Lyon 1, Lyon, France

    Christelle Forcet

Authors
  1. Jean-Marc Vanacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christelle Forcet
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CF drafted the manuscript and prepare the figures. JMV provide critical feedbacks and contributed to the revisions of the manuscript. JMV and CF approved the final version of the manuscript.

Corresponding author

Correspondence to Christelle Forcet.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vanacker, JM., Forcet, C. ERRα: unraveling its role as a key player in cell migration. Oncogene 43, 379–387 (2024). https://doi.org/10.1038/s41388-023-02899-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02899-w

Search

Advanced search

Quick links