There are two main components to this project: development of genetically engineered mouse models (GEMMs) of DCIS and development of imaging techniques for detecting and characterizing preinvasive mammary cancers in mice.Development of GEMMs of DCIS: We are interested in the roles of four key pathways in the progression of DCIS: the Rb, PTEN, p53 and BRCA1 pathways. We genetically disrupt these pathways in the mammary glands of adult mice by using inducible GEMMs. For these mice, the key initiating event is inactivation of the Rb pathway. During this past year, we have investigated several novel methods for Rb inactivation targeting specific epithelial subtypes (keratin 18 and keratin 19) within the mammary gland. In the upcoming year we will use the MMTV promoter to inactivate the Rb pathway as the initiating genetic event, and subsequently determine the role of the BRCA1 and p53 pathways in promoting the progression of DCIS. A key tool we use for studying the progression of preinvasive mammary cancers in mice is noninvasive imaging.Development of new imaging strategies: We are developing a variety of imaging techniques-including magnetic resonance imaging (MRI), ultrasound (US) imaging, and intravital microscopy (IVM)-for the detection and characterization of early stage mammary cancers in mice. The purpose of developing these new imaging techniques is to perform in vivo characterization of early mammary tumorigenesis in GEMMs for which imaging techniques are necessary since early stage cancers are too small to be visible by eye or palpated. During this past year, we have completed a detailed study establishing new MRI and US techniques that can detect preinvasive cancers with very high sensitivity and excellent morphological detail. In the upcoming year we will be developing IVM, fluorescence molecular tomography and contrast enhanced US techniques. These will allow us to quantify molecular and vascular characteristics of preinvasive cancers in vivo.
