Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen

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Abstract
Mammary carcinomas have been induced by 3.5 Gy whole‐body gamma radiation administered at age 40 to 50 days to virgin female Sprague‐Dawley rats. In 142 irradiated controls carcinoma incidence averaged 7.8% in survivors observed less than 300 days and 38.3% of those surviving longer (P < 0.001 by t test). Mammary cancer promotion was inhibited by two methods: estriol (E3) 638 μ/month (2.2 μ/mo) subcutaneously for natural life span begun 2 weeks after exposure reduced cancer incidence from 76% in controls to 48% after 331 to 449 mean days observation until neoplasia was palpable (P < 0.02 by chisquare analysis). Uterine weights were similar in control and treated groups, and were 15% to 18% greater than uteri of nonirradiated controls from other simultaneous experiments. Six monthly 638‐μg doses of 17 alpha ethinyl estriol (EE3) reduced tumors from 88% in controls to 64% (P < 0.05 by chi‐square analysis) and delayed cancer onset (P < 0.01–0.04 by life table analysis). Ethinyl estradiol (EE2) after 6 months' treatment similarly delayed mammary tumor development reducing incidence to 75% (NS), with a six‐fold increase in nonmammary epithelial malignant tumors. Estriol administration begun between 3 days before to 5 days after radiation did not alter mammary cancer incidence in six experiments. Monthly implantation of 2.5 mg tamoxifen (4.44 μ/mo) started 2 weeks after radiation reduced mammary cancer incidence from 83% to 14% after 307 to 314 days' observation (P < 0.001 by chi‐square analysis). Treated rats had atrophic ovaries and uteri consistent with blockade of endogenous estradiol activity. Short‐term parenteral E3 or EE3 therapy using 10 to 30 μ/kg/day (35–100 μm/kg/day) rapidly differentiated virgin rat mammary glands without impairment of subsequent estrus cycles and offers an alternative to castration or life‐long antiestrogen therapy for reduction of risk of radiogenic mammary carcinoma.