Novel mechanisms of antiprogestin action

When hormone antagonists have unexpected 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 receptor 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. By contrast, 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 progestins.