GPER mediates the Egr-1 expression induced by 17β-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells

Breast Cancer Res Treat. 2012 Jun;133(3):1025-35. doi: 10.1007/s10549-011-1901-8. Epub 2011 Dec 7.


Early growth response-1 (Egr-1) is an immediate early gene involved in relevant biological events including the proliferation of diverse types of cell tumors. In a microarray analysis performed in breast cancer cells, 17β-estradiol (E2) and the estrogen receptor antagonist 4-hydroxitamoxifen (OHT) up-regulated Egr-1 through the G protein-coupled receptor named GPR30/GPER. Hence, in this study, we aimed to provide evidence regarding the ability of E2, OHT and the selective GPER ligand G-1 to regulate Egr-1 expression and function through the GPER/EGFR/ERK transduction pathway in both Ishikawa (endometrial) and SkBr3 (breast) cancer cells. Interestingly, we demonstrate that Egr-1 is involved in the transcription of genes regulating cell proliferation like CTGF and cyclin D1 and required for the proliferative effects induced by E2, OHT, and G-1 in both Ishikawa and SkBr3 cells. In addition, we show that GPER mediates the expression of Egr-1 also in carcinoma-associated fibroblasts (CAFs). Our data suggest that Egr-1 may represent an important mediator of the biological effects induced by E2 and OHT through GPER/EGFR/ERK signaling in breast and endometrial cancer cells. The results obtained in CAFs provide further evidence regarding the potential role exerted by the GPER-dependent Egr-1 up-regulation in tumor development and progression. Therefore, Egr-1 may be included among the bio-markers of estrogen and antiestrogen actions and may be considered as a further therapeutic target in both breast and endometrial tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Connective Tissue Growth Factor / genetics
  • Cyclin D1 / genetics
  • Early Growth Response Protein 1 / genetics*
  • Early Growth Response Protein 1 / metabolism
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / metabolism
  • ErbB Receptors / metabolism
  • Estradiol / pharmacology*
  • Estrogen Antagonists / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Promoter Regions, Genetic / drug effects
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology


  • Early Growth Response Protein 1
  • Estrogen Antagonists
  • GPER1 protein, human
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Tamoxifen
  • Cyclin D1
  • Connective Tissue Growth Factor
  • afimoxifene
  • Estradiol
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases