Biphasic effect of short-term pregnancy hormone treatment on N-methyl-N-nitrosourea-induced mammary carcinogenesis in young and old rats

Abstract

This study examined the development of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas in young and old female Lewis rats following short-term treatment with estrogen and progesterone to mimic pregnancy. Rats exposed at 4 weeks of age to MNU were treated at 6 weeks of age (early MNU/young E/P treatment) or at 24 weeks of age (early MNU/old E/P treatment) with a 21-day slow-release pellet containing 0.5 mg 17β-estradiol and 32.5 mg progesterone (E/P). Other rats were exposed to MNU at 22 and again at 23 weeks of age, and were treated with E/P at 24 weeks of age (late MNU/old E/P treatment). All experimental groups were compared with respective MNU-exposed age-matched E/P-untreated rats. Overt mammary carcinomas (≥1 cm in diameter) that were positive for hormone receptors were reduced in young E/P-treated rats, while hormone receptor-negative overt mammary carcinomas increased in old E/P-treated rats. The rate of development of small-sized mammary carcinoma (<1 cm in diameter) was similar in early MNU/young E/P-treated and late MNU/old E/P-treated groups, but higher in early MNU/old E/P-treated rats compared with respective E/P-untreated rats. At the termination of the experiment, normal mammary gland architecture had not been influenced by E/P treatment, although E/P treatment of older rats caused an increase in proliferating cell nuclear antigen (PCNA) labeling of the mammary tissue. Thus, the impact of short-term E/P treatment on MNU-induced rat mammary carcinogenesis is age-dependent and shows biphasic effects; the development of hormone-dependent overt mammary carcinomas was reduced in young rats but the development of hormone-independent overt mammary carcinomas increased in older rats. The enhanced outgrowth of hormone-independent overt mammary carcinomas by E/P treatment in old age is due to accelerated cell proliferation at the promotion/progression phase of mammary carcinogenesis. Age at short-term E/P treatment is crucial for breast cancer control.