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Antagonistic Action between Cyclic Adenosine 3':5'-Monophosphate and Estrogen in Rat Mammary Tumor Growth Control¹

Laboratory of Pathophysiology, National Cancer Institute, NIH, Bethesda, Maryland 20014

Estrogen- and cyclic adenosine 3':5'-monophosphate (cAMP)-binding activities were measured in the biopsy specimens of 35 carcinogen-induced or transplanted rat mammary carcinomas, and the tumor responses to host ovariectomy were followed. The results showed that all of the tumors with high estrogen-binding and low cAMP-binding activities regressed, whereas tumors with either low or high estrogen-binding and high cAMP-binding activites grew following ovariectomy. When 7,12-dimethylbenz()anthracene (DMBA)-induced mammary tumors undergo growth arrest following either ovariectomy or N⁶,O^2'-dibutyryl cyclic adenosine 3':5'-monophosphate (DBcAMP) treatment of the host, a change in the estrogen- and cAMP-binding activities occurred. Three days after either ovariectomy or DBcAMP treatment, cAMP binding increased 5- and 2-fold in the tumor nuclei and cytosol, respectively, whereas nuclear and cytoplasmic estrogen binding decreased by 70 and 25%, respectively. These changes in cAMP- and estrogen-binding activities were detectable within 1 day after either ovariectomy or DBcAMP treatment, and the changes were reversed when resumption of tumor growth was induced by the injection of estradiol valerate or cessation of DBcAMP treatment. When DMBA tumors failed to regress after either ovariectomy or DBcAMP treatment, the change in estrogen- and cAMP-binding activities did not occur. Concomitant with the increase of cAMP-binding activity in regressing tumors were increases in protein kinase activity and cAMP content of the tumors. New phosphorylation of a nonhistone nuclear protein also occurred in regressing DMBA tumors but ceased when tumor growth was resumed after injection of estradiol valerate or cessation of DBcAMP treatment. Phosphorylation of the regression-associated protein was induced in vitro by preincubation of growing DMBA tumor slices with 10^-5 M cAMP and was inhibited by the simultaneous addition of 10^-7 M 17ß-estradiol with cAMP. These data suggest an interaction between a steroid hormone and cAMP in the growth control of a hormone-dependent mammary tumor.

¹ Presented at the John E. Fogarty International Center Conference on Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md.