ERα36-GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Int J Mol Sci. 2021 Jul 16;22(14):7603. doi: 10.3390/ijms22147603.


Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.

Keywords: GPER1; IL-6; NF-κB; TLR4; TNFα; breast cancer; estrogen receptor alpha 36.

MeSH terms

  • Breast Neoplasms
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor alpha / physiology
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inflammation / metabolism
  • Interleukin-6 / metabolism
  • MCF-7 Cells
  • Monocytes / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Receptors, Estrogen / metabolism*
  • Receptors, Estrogen / physiology
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, G-Protein-Coupled / physiology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • GPER1 protein, human
  • Interleukin-6
  • NF-kappa B
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • estrogen receptor alpha 36, human
  • Estradiol