Abstract
6073
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 used a transplantable model for mammary hyperplasia that progresses to invasive carcinoma, effectively mimicking human ductal carcinoma in situ (DCIS), to study molecular changes associated with neoplastic progression. This provides a unique model for chemoprevention trials for high-risk pre-malignant breast lesions. These mouse mammary intraepithelial neoplasia-outgrowth lines (MIN-Os) were derived from the mammary hyperplasia of MMTV-polyomavirus middle T (MT) transgenic mice. The MT transgene is a potent oncogene and provides an attractive model for human mammary carcinoma, as it is capable of transforming cells by the same signaling pathways activated by receptor tyrosine kinases, such as erbB2, which has been dysregulated in human breast cancer. Gene expression analysis of preneoplastic MIN-O lesions and associated tumors from these lines find dysregulation of genes and pathways that are similarly altered in human DCIS. Moreover, global expression profile analysis suggests that major molecular changes are already in place at the MIN-O stage. This result is in agreement with what is reported in human studies. We have begun using this model to dissect the events that are required for the transition from preneoplasia to invasive carcinoma. In addition, we are developing chemoprevention strategies for these high-risk breast lesions. Preliminary experiments show that treatment with either estrogen receptor modulators or rapamycin is effective in significantly limiting growth (p<0.001, p<0.05 respectively) but does not eradicate the lesion (see figure 1). We are now developing alternative strategies that provide more effective therapy with the goal of totally eliminating the disease. This mouse model provides a platform that is amenable for the molecular dissection of the genes involved in progression and for chemoprevention pre-clinical trials, with easily measurable end-points for testing effectiveness of agents, while providing tissue for correlative molecular studies.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]
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