PITUITARY-ISOGRAFTED MICE ARE HIGHLY SUSCEPTIBLE TO MNU-INDUCED MAMMARY CARCINOGENESIS IRRESPECTIVE OF THE LEVEL OF ALVEOLAR DIFFERENTIATION

We have recently developed a mammary tumorigenesis system in which adu lt female BALB/c mice are grafted with two pituitaries from isologous donors and subsequently treated with a single i.v. injection of N-meth yl-N-nitrosourea (MNU, 50 mg/kg). Mice bearing isografts have elevated serum titers of prolactin and progesterone which act on the mammary g lands to produce a highly differentiated morphology resembling that of late pregnancy. MNU treatment of the mouse mammary gland in this diff erentiated state results in tumors in >90% of tested animals. Since th e mammary gland is believed to be particularly vulnerable to chemicall y induced carcinogenesis during alveolar morphogenesis, we chose to as sess 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 isogra fted with pituitaries and subsequently analyzed at 1, 3, 5, 8 and 12 w eeks for epithelial cell differentiation and susceptibility to MNU-ind uced tumorigenesis. By 3 weeks after isografting, the glands showed ma rked lobuloalveolar development and highest casein production. Tumor l atency and frequency paralleled parenchymal differentiation for the fi rst 3 weeks. By 5 weeks, and thereafter, the mice continued to be extr emely susceptible to MNU-induced mammary carcinogenesis despite the hi ghly differentiated state of the glands. Since tumors generated in thi s system are not dependent on pituitary isografts for their growth whe n transplanted to isologous recipients, and since the pituitary isogra ft does not act as a classical promoter but is required at the time of carcinogen treatment, we conclude that the pituitary isograft maintai ns a condition permissive for transformation to occur and a level of p roliferation sufficient for the expression of the transformed phenotyp e.