The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.
The protein kinase A stimulator cAMP can potentiate the ability of progestins to induce the transactivation function of the human progesterone receptor (hPR). We questioned in the present study whether cAMP could functionally cooperate with the progestin antagonist RU486. In T47D human breast cancer cells, RU486 behaves as a pure antagonist with respect to induction of the progesterone-responsive mouse mammary tumor virus chloramphenicol acetyltransferase (MMTV-CAT) reporter gene. It fails to stimulate MMTV-CAT expression and completely inhibits induction by the synthetic progestin R5020. However, when RU486 is combined with 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), MMTV-CAT is induced to levels approaching that stimulated by R5020 alone. Also, RU486 in the presence of 8-Br-cAMP is only partially effective in antagonizing R5020 action. The agonist activity exhibited under these conditions appears to be due to RU486 acting through hPR as evidenced by the fact that 8-Br-cAMP alone has no effect on MMTV-CAT, whereas induction by the combination of 8-Br-cAMP and RU486 is dose responsive to RU486 in a saturable manner and can be inhibited by the type I antiprogestin (prevents hPR-DNA binding) ZK98299, which does not exhibit positive functional cooperation with cAMP. Acquisition of agonist activity in the presence of 8-Br-cAMP also extends to the type II antiprogestin (permits hPR-DNA binding) ZK112993. Since RU486 is also a type II antagonist, these results suggest that detection of functional synergism between cAMP and antiprogestins may require binding of the hPR-antagonist complex to DNA. We propose that cross-talk between second messenger and steroid receptor signal transduction pathways may be one mechanism for resistance to steroid antagonists that frequently develops in breast cancer.
Department of Pathology, University of Colorado Health Sciences Center, Denver 80262.
C A
CA
Beck
N L
NL
Weigel
M L
ML
Moyer
S K
SK
Nordeen
D P
DP
Edwards
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology*; D011374:Progesterone / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011980:Receptors, Progesterone; C064879:ZK 112993; D015124:8-Bromo Cyclic Adenosine Monophosphate; D015735:Mifepristone; D011374:Progesterone; D000242:Cyclic AMP