Methylguanine methyltransferase activity deficiency parallels the increased susceptibility of mammary epithelial cells from sexually immature rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea

It is known from studies of women irradiated at the atomic bombings of Hiroshima and Nagasaki, and for the treatment and diagnosis of medical conditions, that the immature human breast is more susceptible than the mature breast to the carcinogenic effects of ionizing radiation. Other risk factors, including nulliparity or late age at first birth, imply that functional differentiation of the breast is protective against breast cancer; indeed, there are advocates of hormonally inducing differentiation of the breast as a protective preventative measure. Even in the face of this information, though, most epidemiological studies still focus on exposures of adult, postpubertal women in the search for avoidable human breast carcinogens. The work reported here was undertaken in order to explore, using the Fischer 344 rat as a model, the age-differential susceptibility of the breast to chemically-induced carcinogenesis, lethality, and mutagenesis. Mammary epithelial cells (MECs) from sexually immature (3-week-old) rats were more susceptible than those of sexually mature (8-week-old) rats to the carcinogenic, lethal, and mutagenic effects of the alkylating agent N-nitroso-N-methylurea (NMU). The effect was carcinogen-specific, since immature rats were less susceptible to the carcinogenic effects of the polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA), and there was no effect of age on MEC lethality induced by DMBA. The etiology of the age-differential effects of NMU was explored, and it was found that similar mutagenic effects (primarily GC→AT transition mutations) happen more often in the immature than the mature MECs. The significant deficiency of the immature MECs in the activity of methylguanine methyltransferase (MGMT), the primary enzyme responsible for the repair the highly mutagenic O 6-methylguanine (meG) lesion produced by NMU treatment, parallels the increased susceptibility of the immature rat mammary gland to all the effects of NMU studied. These results suggest that the immature human breast could also be more susceptible to at least selected breast carcinogens, as it is to ionizing radiation. These studies provide the scientific rationale for studying mechanistically and epidemiologically the age-related susceptibility of the human breast to certain chemical classes beginning with alkylating agents, which are present in the diet, cigarette smoke, and are used as chemotherapy.