Pituitary-isografted mice are highly susceptible to MNU-induced mammary carcinogenesis irrespective of the level of alveolar differentiation.

Abstract

We have recently developed a mammary tumorigenesis system in which adult female BALB/c mice are grafted with two pituitaries from isologous donors and subsequently treated with a single i.v. injection of N-methyl-N-nitrosourea (MNU, 50 mg/kg). Mice bearing isografts have elevated serum titers of prolactin and progesterone which act on the mammary glands to produce a highly differentiated morphology resembling that of late pregnancy. MNU treatment of the mouse mammary gland in this differentiated state results in tumors in > 90% of tested animals. Since the mammary gland is believed to be particularly vulnerable to chemically induced carcinogenesis during alveolar morphogenesis, we chose to assess the susceptibility of the mammary gland during the initial weeks after pituitary isografting when they are ostensibly undergoing marked cell proliferation and differentiation. To this end, mice were isografted with pituitaries and subsequently analyzed at 1, 3, 5, 8 and 12 weeks for epithelial cell differentiation and susceptibility to MNU-induced tumorigenesis. By 3 weeks after isografting, the glands showed marked lobuloalveolar development and highest casein production. Tumor latency and frequency paralleled parenchymal differentiation for the first 3 weeks. By 5 weeks, and thereafter, the mice continued to be extremely susceptible to MNU-induced mammary carcinogenesis despite the highly differentiated state of the glands. Since tumors generated in this system are not dependent on pituitary isografts for their growth when transplanted to isologous recipients, and since the pituitary isograft does not act as a classical promoter but is required at the time of carcinogen treatment, we conclude that the pituitary isograft maintains a condition permissive for transformation to occur and a level of proliferation sufficient for the expression of the transformed phenotype.