title: Surprises with antiprogestins: novel mechanisms of progesterone receptor action.
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.
authors.affiliation: University of Colorado Health Sciences Center, Department of Medicine, Denver 80262, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Horwitz
authors.forename: C A
authors.initials: CA
authors.lastname: Sartorius
authors.forename: A R
authors.initials: AR
authors.lastname: Hovland
authors.forename: T A
authors.initials: TA
authors.lastname: Jackson
authors.forename: S D
authors.initials: SD
authors.lastname: Groshong
authors.forename: L
authors.initials: L
authors.lastname: Tung
authors.forename: G S
authors.initials: GS
authors.lastname: Takimoto
mesh_terms: 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
chemical_list: D006727:Hormone Antagonists; D011980:Receptors, Progesterone; D000242:Cyclic AMP