Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Endocr Relat Cancer. 2019 Aug;26(8):R479-R497. doi: 10.1530/ERC-19-0132.


Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

Keywords: androgen insensitivity syndromes (AIS); androgen receptor; glucocorticoid receptor; hormone resistance; ligand-binding domain; multimerization; prostate cancer; protein structure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Androgen-Insensitivity Syndrome / etiology
  • Androgen-Insensitivity Syndrome / metabolism*
  • Androgen-Insensitivity Syndrome / pathology
  • Humans
  • Male
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Multimerization
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Mineralocorticoid / chemistry
  • Receptors, Mineralocorticoid / genetics
  • Receptors, Mineralocorticoid / metabolism
  • Receptors, Progesterone / chemistry
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Receptors, Thyroid Hormone / chemistry
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Steroids / metabolism


  • AR protein, human
  • Receptors, Androgen
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Receptors, Mineralocorticoid
  • Receptors, Progesterone
  • Receptors, Thyroid Hormone
  • Steroids