Regression of hormone-dependent mammary tumors in Sprague-Dawley rats as a result of tamoxifen or pharmacologic doses of 17 beta-estradiol: cyclic adenosine 3',5'-monophosphate-mediated events.
The estrogen and cyclic adenosine 3',5'-monophosphate (cAMP)-binding activities changed markedly when 7,12-dimethylbenz[a]anthracene-induced mammary tumors of Sprague-Dawley rats regressed following daily injections of either tamoxifen or pharmacologic doses of 17 beta-estradiol. cAMP binding increased eightfold to tenfold, whereas estrogen binding increased twofold to threefold in regressing tumor nuclei at 5 days after either treatment, which resulted in an inversion of the ratio of estrogen binding to cAMP binding found in growing tumor nuclei. Concomitantly, both binding activities were depleted from the cytosol. In the regressing tumors, the cAMP level increased twofold and nuclear cAMP-dependent protein kinase activity increased threefold to fourfold, with a 70-80% decrease in the cytoplasmic protein kinase activity. The rise in the nuclear protein kinase activity was abolished when cycloheximide was given with tamoxifen or with high doses of 17 beta-estradiol, which suggests that the increased activity is due to new protein synthesis. In the regressing tumor nuclei, the phosphorylation of the regression-associated proteins increased, whereas the phosphorylation of growth-associated proteins decreased. These data suggest that the mammary tumor regression induced by tamoxifen or high doses of estrogen proceed through a series of cAMP-mediated events.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology*
D013629:Tamoxifen; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D000242:Cyclic AMP; D011494:Protein Kinases