Gene expression profiling of a transplantable model of preneoplastic progression in mice using p53-null mammary epithelial cells

We show that macrophages are recruited to ductal hyperplasias that have a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention. To investigate mechanisms that drive tumorigenesis in early breast cancer progression, we employed a transplantable model of preneoplastic progression. Transplantation of p53-null mammary epithelial cells into the cleared mammary fad pads of syngeneic wildtype mice led to the formation of several premalignant lines that histologically and genetically recapitulated the various subtypes of human breast cancer. Two of these lines, PN1a and PN1b, were derived from contralateral outgrowths from the same mouse, and tissue from these outgrowths was serially transplanted for over 10 generations to confirm stability. At 16 weeks post-transplantation, PN1a lesions develop a poorly differentiated, lobuloalveolar morphology with multifocal regions of atypical cells in solid nests, while PN1b lesions remain low grade, ductal hyperplasia. hyperplasia I (PN1a) group and hyperplasia 2 (PN1b) group