Genomic Function of Estrogen Receptor β in Endometriosis

Endocrinology. 2019 Nov 1;160(11):2495-2516. doi: 10.1210/en.2019-00442.


Estrogen receptor (ER) β plays a critical role in endometriosis progression because cytoplasmic ERβ stimulates proinflammatory signaling in ectopic lesions and prevents apoptosis to promote their survival. However, the role of "nuclear ERβ" in endometriosis progression is not known. This critical knowledge gap obscures our understanding of the full molecular etiology of ERβ-mediated endometriosis progression. To fill this void, we generated an ERβ-regulated transcriptome and ERβ cistrome in ectopic lesions and the eutopic endometrium of mice with endometriosis by using a new endometrium-specific FLAG-tagged human ERβ overexpression mouse model. The integration of these omics data sets revealed that ERβ stimulated the proliferation activities of ectopic lesions and the eutopic endometrium by directly upregulating MYC and E2 transcription factor target genes and genes associated with the G2/M transition. Additionally, ERβ stimulated gene expression associated with TNFα/nuclear factor κB (NF-κB) signaling, epithelial-mesenchymal transition, reactive oxygen species signaling, IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling, and hypoxia signaling and suppressed IFNα signaling in ectopic lesions to enhance endometriosis progression. ERβ also stimulated gene expression associated with the unfolded protein response and IL-6/JAK/STAT3 inhibitory signaling and suppressed TNFα/NF-κB signaling in the eutopic endometrium to cause endometriosis-associated endometrial dysfunction. Therefore, nuclear ERβ-regulated gene networks provide critical clues to understand the molecular etiology and complexity of endometriosis and endometriosis-associated endometrial dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endometriosis / metabolism*
  • Endometrium / metabolism
  • Estrogen Receptor beta / metabolism*
  • Female
  • Gene Expression Regulation*
  • Gene Regulatory Networks*
  • Humans
  • Interferons / metabolism
  • Mice, Inbred C57BL


  • Estrogen Receptor beta
  • Interferons