Genetic differences in estrogen-induced deoxyribonucleic acid synthesis in the rat pituitary: correlations with pituitary tumor susceptibility.

Anterior pituitary nuclei isolated from rats were used in an in vitro DNA synthesis assay. The rate of in vitro synthesis was increased by prior in vivo estrogen treatment in a time-dependent and dose-dependent manner, and the observed increase was similar in magnitude to that measured by [3H] thymidine incorporation in whole tissue. In vitro DNA synthesis was sensitive to N-ethylmaleimide but resistant to dideoxythymidine triphosphate. Rates of pituitary DNA synthesis were compared in the Fischer 344 (F344) rat, a strain highly susceptible to diethylstilbestrol-induced pituitary tumors, and in the Holtzman rat, a strain resistant to rapid tumor induction by diethylstilbestrol. After chronic treatment (8 weeks) with estrogen, elevated DNA synthesis (2- to 3-fold) was observed in F344 pituitaries but not in Holtzman pituitaries. After short term (2-4 days) treatment with estrogen, however, DNA synthesis increased 2-fold in both Holtzman and F344 pituitary nuclei. The elevated DNA synthesis declined in the Holtzman strain after 5 or 6 days of additional estrogen treatment, but elevated DNA synthesis persisted in the F344 strain. These results suggest that the genetic difference is due to the lack of a proliferation control mechanism in the F344 strain that functions in the Holtzman strain to shut off estrogen-stimulated cell proliferation.