The molecular biology of mammary intraepithelial neoplasia outgrowths

Genetically engineered mice have been used extensively to model human breast cancer. Yet few have been developed and characterized to model the progression from hyperplasia to cancer. We have developed a transplantable model for mammary hyperplasia that progresses to invasive carcinoma, effectively mimicking human ductal carcinoma in situ (DCIS). As such, this provides a unique model for chemoprevention trials for high-risk premalignant breast lesions. These transplantable lines, also known as mammary intraepihelial neoplasia outgrowths (MIN-Os), were developed by our group and are derived from the mammary hyperplasia of mouse mammary tumor virus-polyomavirus middle T (mT) transgenic mice. The polyomavirus transgene provides an attractive model for human mammary carcinoma, as it is capable of transforming cells by triggering signal transduction pathways that have been implicated to be activated by erbB2, through interactions between its mT gene product and key cellular signaling proteins–such as c-Src, Shc, and phosphatidylinositol 3-kinase, which have all been implicated as important in human breast cancer. These transplanted lines are heterogeneous; however, within a line, through multiple generations, the MIN-Os show consistent growth rate, histopathology, and latency to tumor formation. The lines and the tumors that arise from them maintain their defining characteristics in 'tests by transplantation'. Histopathologically, the MIN-Os resemble human DCIS, and the resulting mammary invasive carcinoma resembles human invasive ductal carcinoma. With gene expression studies, we have found dysregulated genes and pathways that have been shown to be similarly altered in human DCIS, suggesting that our model is related to DCIS not only at a histopathological level, but also at a molecular level. These gene expression studies suggest the importance of stromal–epithelial interactions, the extracellular matrix proteoglycan-mediated regulation of cell proliferation signaling, actin cytoskeleton organization, and the insulin-like growth factors and their effectors in the transition from hyperplasia to transformed invasive carcinoma. We have begun using this human DCIS model for developing chemoprevention strategies for high-risk breast lesions. With in vitro assays, we have ranked inhibitors for effectiveness and inclusion in in vivo studies. We have demonstrated that inhibitors to phosphatidylinositol 3-kinase and related downstream mediators are effective in inhibiting growth. This mouse model provides an attractive platform that is amenable to interventional studies and chemoprevention preclinical trials, with easily measurable end-points for testing effectiveness of agents while providing tissue for correlative molecular studies.