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.
Horwitz
K B
KB
University of Colorado Health Sciences Center, Department of Medicine, Denver 80262, USA.
Tung
L
L
Takimoto
G S
GS
D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D011372:Progestins / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011372:Progestins; D011980:Receptors, Progesterone; D000242:Cyclic AMP