Effects of Different Durations of Estrogen and Progesterone Treatment on Development of N-methyl-N-nitrosourea-induced Mammary Carcinomas in Female Lewis Rats

Abstract

Background: There have been no precise evaluations of the effects of different durations of exposure to estrogen and progesterone pregnancy levels on mammary carcinogenesis risk. We examined such effects on the development of N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma. Materials and Methods: Female Lewis rats were administered a single intraperitoneal injection of 50 mg/kg MNU at 28 days of age, and then were either left hormone-untreated (control group), or underwent subcutaneous implantation of a 21-day release pellet containing 0.5 mg 17β-estradiol and 32.5 mg progesterone (E/P pellet) at 42 days of age. The pellet was either replaced every 3 to 4 weeks throughout the experimental period (long-term E/P group), or was implanted only once (short-term E/P group). Circulating 17β-estradiol and progesterone levels in the serum, and expression of estrogen receptor (ER) α and progesterone receptor (PgR) in the normal mammary gland were measured. The rats were sacrificed when they developed a mammary tumor with a diameter of ≥1 cm, or when they reached the age of 29 weeks. Results: In rats implanted with a single E/P pellet, circulating 17β-estradiol and progesterone levels were significantly elevated 2 weeks after implantation, but returned to control levels 8 weeks after implantation; 17β-estradiol transiently reached pregnancy levels. In normal mammary glands of rats sacrificed at 29 weeks of age, both long- and short-term E/P treatment decreased the percentage of ERα- and PgR-positive cells. Rats that received long- or short-term E/P treatment had a decreased incidence of mammary carcinoma with a diameter of ≥1 cm, compared to control rats. However, when histologically detected microcarcinomas (diameter <1 cm) were included for comparison, the E/P-treated groups exhibited an abrupt increase in the number of microcarcinomas from 22 to 25 weeks after MNU injection. Although short-term E/P treatment significantly suppressed mammary carcinomas of all sizes, long-term E/P treatment had no cancer-suppressing effect. Conclusion: The duration of E/P treatment is an essential factor for the suppression of mammary carcinogenesis.