The Principal Investigator has developed a mouse mammary tumor model derived from transgenic mice constructed with the polyoma virus (PyV) middle T (mT) and related site specific mutations, that mimic the neoplastic progression of breast carcinoma from its inception to metastasis. The PyV-mT transgene, which can activate a number of genes, but in particular it activates phosphatidylinositol - 3 - kinase (PI3-K) and its related pathways, is a uniquely appropriate and biologically relevant transgene for modeling human breast cancer, since the c-erbB family of tyrosine kinases, which have been shown to activate PI3-K, have been implicated in human breast cancer. This proposal focuses on two major aspects of determining the biology of this model. The first is to develop transplantable outgrowth lines from selected histologic stages of neoplastic transformation and characterize their biological potential by serial transplantation. The second is to dissect the molecular pathways involved in the progression of breast cancer from the benign state to the metastasis by comprehensive gene expression profiling. In particular, they plan to test the hypothesis that the PI3-K and/or downstream signaling intermediates are key regulators of neoplastic transformation, tumor development, and metastasis in the mouse mammary tumor model. The goal of this project is to develop a well-characterized model for breast cancer development and to dissect the molecular pathways involved in tumor formation.
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