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 progressi on from N-methyl-N-nitrosourea (MNU)-induced hyperplastic lesions. Nin ety-one percent of transplanted mammary tumors grew, with an orthotopi c 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, repres entative of those found in the rat mammary gland after MNU-treatment. Hyperplasias developed into neoplasias that were both hormone dependen t 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 asso ciated with an elevated tumorigenic potential. Our observations sugges t that there are multiple histopathogenic pathways in the development and progression to hormone independent rat mammary tumors.