Estradiol-17 beta as an initiation modifier for radiation-induced mammary tumorigenesis of rats ovariectomized before...

This investigation evaluated the roles of estradiol-17 beta, progesterone and prolactin in the initiation of mammary tumorigenesis by irradiation. Sixty day old Wistar-MS rats ovariectomized bilaterally at 23 days of age were injected daily with olive oil, estradiol-3-benzoate (E2B), progesterone or haloperidol for 14 days, and were then irradiated with gamma-rays (260 cGy) on the morning following the last injection. Diethylstilbestrol pellets were administered by implantation 30 days after the irradiation. Following treatment with E2B, the incidence of mammary tumors was increased 2.2-fold, in comparison with that in the corresponding control rats. Bilateral ovariectomy before puberty caused the mammary glands of adult rats to atrophy, and a low degree of differentiation with long narrow ducts was observed in whole mounts. The DNA synthesis in the mammary glands and serum prolactin level of E2B-treated rats were markedly increased and the terminal ducts showed distinctly increased differentiation into terminal end buds and alveolar buds with prolactin receptors. When progesterone, another ovarian hormone, or haloperidol, a dopamine antagonist in adenohypophysis, was injected into the rats under estrogen-free conditions, neither expression of prolactin receptors nor stimulation of DNA synthesis was observed in the mammary glands, and the incidence of mammary tumors induced by irradiation was lower than that observed in rats treated with E2B. Combined treatment with E2B and progesterone resulted in a reduction in the incidence of mammary tumors and in serum prolactin levels compared with those in E2B alone, in spite of the synergistic effects on prolactin receptor concentration and DNA synthesis by the two hormones. On the other hand, concurrent administration of haloperidol did not reduce the E2B-induced tumor incidence or prolactin concentration in serum. Many of the mammary tumors which developed in the ovariectomized rats were of the ER(-)PgR(-) type. The incidence of development of ER(+)PgR(+) tumors was increased by treatment with E2B before the irradiation, and no ER(-)PgR(-) tumors were observed in this group. Our results suggest that estrogen is a direct or indirect sensitizer for tumor initiation by radiation, and is also one of the regulatory factors for hormone dependence of radiation-induced mammary tumors.