Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia?

Administration of a single i.v. injection of 50 mg N-methyl-N-nitrosourea (MNU)/kg body wt to 50- to 60-day old virgin rats, 120-day-old virgin rats, and 120-day-old parous rats (Sprague-Dawley; n = 18-37) resulted in a high incidence of mammary carcinomas in the virgin animals (97.3% in 50- to 60-day-old virgin rats; 75.0% in 120-day-old virgin rats), but mammary carcinomas did not develop in the parous rats. The concentrations in serum of various mammotropic hormones were measured in identical groups of rats at the time of MNU treatment. Growth hormone (GH) concentration was significantly reduced in parous rats, as compared with young or age-matched virgin rats. The concentrations of prolactin, 17 beta-estradiol, progesterone, corticosterone and thyroxine were not significantly altered in the parous rats compared to the two groups of virgin animals. Histological examination of the mammary glands from the three groups of rats showed that the epithelia of the parous animals were in a stage of regression, whereas the mammae of the young virgin rats showed the highest degree of lobulo-alveolar development. The levels of estrogen receptor (ER), epidermal growth factor (EGF) receptor (EGF-R) and GH receptor (GHR) in the mammary glands of the animals were also measured. We found a reduction in the receptor levels for both estrogen and EGF in mammary tissues from parous animals. Receptors for GH were present in normal mammary tissues from both virgin and parous rats. We hypothesize that the reduction in the circulating concentration of GH caused the reduced susceptibility of parous rats to mammary carcinogenesis possibly by decreasing the levels of ER and/or EGF-R in the mammary gland.