Surprises with antiprogestins: novel mechanisms of progesterone receptor action

Ciba Found Symp. 1995;191:235-49; discussion 250-3. doi: 10.1002/9780470514757.ch14.

Abstract

When hormone antagonists have inappropriate agonist-like effects, the clinical consequences are grave. We describe novel molecular mechanisms by which antiprogestin-occupied progesterone receptors behave like agonists. These mechanisms include agonist-like transcriptional effects that do not require receptor binding to DNA at progesterone response elements, or that result from cross-talk between progesterone receptors and other signalling pathways. We discuss the complex structural organization of progesterone receptors, and demonstrate that the B receptor isoform has a unique third activation domain that may confer agonist-like properties in the presence of antiprogestins, whereas the A receptor isoform is a dominant-negative inhibitor. We argue that these novel mechanisms play a role in the apparent hormone resistance of breast cancers and the variable tissue-specific responses to antagonists.

Publication types

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

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cyclic AMP / physiology
  • Hormone Antagonists / pharmacology*
  • Humans
  • Receptors, Progesterone / antagonists & inhibitors*
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Hormone Antagonists
  • Receptors, Progesterone
  • Cyclic AMP