Surprises with antiprogestins: novel mechanisms of progesterone receptor action.
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.
Horwitz
K B
KB
University of Colorado Health Sciences Center, Department of Medicine, Denver 80262, USA.
Sartorius
C A
CA
Hovland
A R
AR
Jackson
T A
TA
Groshong
S D
SD
Tung
L
L
Takimoto
G S
GS
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D006727:Hormone Antagonists; D011980:Receptors, Progesterone; D000242:Cyclic AMP