Progestagens and mammary gland development: differentiation versus carcinogenesis

The role of hormones, especially progesterone and synthetic progestins, in the pathogenesis of breast cancer is highly debated and far from being clarified. The observation that differentiation of the mammary gland prior to exposure to a carcinogenic agent inhibits the initiation of mammary carcinomas, and the fact that this protection is mediated by cell kinetic changes induced in the gland parenchyma by hormonal stimuli such as that of pregnancy, led us to determine how ovariectomy and hormonal supplementation affect the cell kinetic characteristics in various terminal ductal structures of an intact animal mammary gland, i.e., terminal end buds, terminal ducts and alveolar buds. Fifty-day-old virgin Sprague-Dawley rats were either ovariectomized or treated for 21 days with norethynodrel and mestranol or medroxyprogesterone acetate in doses of 0.5 mg (low dose - LD), or 5.0 mg (high dose - HD); chorionic gonadotropin (hCG) in doses of 1 or 100 IU/day, or placental lactogen (PL) in a dose of 0.5 mg. Cell kinetics were studied by counting the number of cells incorporating [3H]-thymidine and expressed as the DNA labeling index. In the intact animal, the rate of cell proliferation was highest in terminal end buds, decreased progressively towards the ductal portions and was even lower in alveolar buds. Ovariectomy significantly reduced the proliferative activity of the mammary epithelium, ten-fold in terminal ducts and alveolar buds, and five-fold in terminal end buds. DNA labeling index was significantly reduced in terminal ducts and alveolar buds by all hormones at all doses, except PL.(ABSTRACT TRUNCATED AT 250 WORDS)