Chemoprevention of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17 beta-estradiol and progesterone.

Because hormones of pregnancy are thought to alter the mammary gland such that the epithelial cells are less susceptible to future carcinogenic insults, the present study was conducted to determine the ability of short-term treatment with 17 beta-estradiol and/or progesterone, administered immediately after puberty, to prevent mammary cancers in rats subsequently exposed to N-nitroso-N-methylurea [(NMU) CAS:684-93-5]. Beginning at 40 days of age, female outbred Sprague-Dawley rats received 20 micrograms 17 beta-estradiol and/or 4 mg progesterone for 5 weeks. NMU (50 mg/kg body wt) was administered at 96 and 103 days of age (3 and 4 wk, respectively, after the last hormone injection). Pretreatment of rats with 17 beta-estradiol plus progesterone was highly effective in preventing mammary cancer induction (88% fewer cancers compared to the cancer incidence in rats pretreated with the hormone vehicle). Wholemounts of the mammary glands of rats treated with 17 beta-estradiol plus progesterone revealed that the gland was stimulated to a highly differentiated state (similar to that observed in late pregnancy). At the time of NMU treatment, the gland had involuted but was quite different from controls; i.e. an absence of terminal end buds and terminal ducts was noted. The short-term treatment with hormones did not induce tumors and did not interfere with subsequent reproductive and lactational performance. It is apparent that stimulation of the mammary gland to a highly differentiated state early in life can provide protection against future carcinogen exposure.