Hormone dependent and independent mammary tumor development from N-methyl-N-nitrosourea-treated rat mammary epithelial cell xenografts in the nude mouse: multiple pathways and H-ras activation

A nude mouse mammary fat pad xenograft system was developed to examine hormone dependent and independent mammary tumorigenesis and progression from N-methyl-N-nitrosourea (MNU)-induced hyperplastic lesions. Ninety-one percent of transplanted mammary tumors grew, with an orthotopic preference, and maintained their hormone dependence, histopathology, and H-ras mutation frequency. Grafted mammary epithelial cells, from MNU-treated rats, developed normal and hyperplastic outgrowths, representative of those found in the rat mammary gland after MNU-treatment. Hyperplasias developed into neoplasias that were both hormone dependent and independent. We demonstrate that hormone independent tumors can develop directly either from lobuloalveolar or ductal hyperplasias or from hormone dependent tumors. H-ras mutation was detected in mammary preneoplasias (4 lines) before they developed into tumors and was associated with an elevated tumorigenic potential. Our observations suggest that there are multiple histopathogenic pathways in the development and progression to hormone independent rat mammary tumors.