The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis

Hum Reprod Update. Jul-Aug 2014;20(4):467-84. doi: 10.1093/humupd/dmu002. Epub 2014 Mar 14.

Abstract

Background: Endometriosis is defined as the colonization and growth of endometrial tissue at anatomic sites outside the uterine cavity. Up to 15% of reproductive-aged women in the USA suffer from painful symptoms of endometriosis, such as infertility, pelvic pain, menstrual cycle abnormalities and increased risk of certain cancers. However, many of the current clinical treatments for endometriosis are not sufficiently effective and yield unacceptable side effects. There is clearly an urgent need to identify new molecular mechanisms that critically underpin the initiation and progression of endometriosis in order to develop more specific and effective therapeutics which lack the side effects of current therapies. The aim of this review is to discuss how nuclear receptors (NRs) and their coregulators promote the progression of endometriosis. Understanding the pathogenic molecular mechanisms for the genesis and maintenance of endometriosis as modulated by NRs and coregulators can reveal new therapeutic targets for alternative endometriosis treatments.

Methods: This review was prepared using published gene expression microarray data sets obtained from patients with endometriosis and published literature on NRs and their coregulators that deal with endometriosis progression. Using the above observations, our current understanding of how NRs and NR coregulators are involved in the progression of endometriosis is summarized.

Results: Aberrant levels of NRs and NR coregulators in ectopic endometriosis lesions are associated with the progression of endometriosis. As an example, endometriotic cell-specific alterations in gene expression are correlated with a differential methylation status of the genome compared with the normal endometrium. These differential epigenetic regulations can generate favorable cell-specific NR and coregulator milieus for endometriosis progression. Genetic alterations, such as single nucleotide polymorphisms and insertion/deletion polymorphisms of NR and coregulator genes, are frequently detected in ectopic lesions compared with the normal endometrium. These genetic variations impart new molecular properties to NRs and coregulators to increase their capacity to stimulate progression of endometriosis. Finally, post-translational modifications of NR coregulators, such as proteolytic processing, generate endometriosis-specific isoforms. Compared with the unmodified coregulators, these coregulator isoforms have unique functions that enhance the pathogenesis of endometriosis.

Conclusions: Epigenetic/genetic variations and posttranslational modifications of NRs and coregulators alter their original function so that they become potent 'drivers' of endometriosis progression.

Keywords: endometriosis; nuclear receptor; nuclear receptor coregulator.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cytokines / physiology
  • DNA Methylation / genetics
  • DNA Methylation / physiology
  • Disease Progression
  • Down-Regulation / physiology
  • Endometriosis / genetics*
  • Estrogens / genetics
  • Estrogens / physiology
  • Female
  • Gene Expression / genetics
  • Gene Expression / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mice
  • Progesterone / physiology
  • Protein Processing, Post-Translational / genetics
  • Protein Processing, Post-Translational / physiology
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Cytokines
  • Estrogens
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Progesterone