Our research focuses on the biochemical basis for growth, survival and transformation of mammary epithelial cells.  We concentrate on the following areas: 1. The study of genes that are associated with breast cancer and the exploration of signaling pathways regulated by them during initiation, progression and metastasis. To evaluate the role of signaling proteins, such as Akt family genes, at the level of the whole animal, we delete the gene encoding the protein of interest in mice and characterize the effects on growth and tumor formation. Thus, we are testing the severity of mammary tumors and the possibility that tumor development could be reduced in genetic backgrounds lacking functions of the Akt isoforms in transgenic animal models that are predisposed to breast cancer, via the reproduction of genetic alterations present in human tumors, including HER2/Neu and Wnt-1. Currently, the research in our lab has focused on the establishment of genetic systems that permit the cell-specific and temporal inactivation and reactivation of genes in the mouse.      We aim to 1) address upstream and downstream signaling pathways involved in the mediation of Akt-specific isoform function in normal development and tumor progression, 2) identify in vivo targets of each Akt isoforms that is implicated in processes of cancer progression with particular emphasis on metastasis-associated genes, and 3) determine whether Akt function correlates with cell-type and specific stages of breast cancer pathogenesis. 2. The role of breast cancer-related genes in the developmental biology of the mammary gland.  In addition to studying oncogenic effects of these mutations, we are interested in the developmental consequences of the loss of function of these genes during normal mammary gland development. An understanding of the homozygous mutant phenotype may provide clues to the function of these genes in normal cells and help explain how their loss contributes to carcinogenesis. 3. Epithelial and Mesenchymal activities of the breast cancer related genes. Of particular interest is the interaction between stroma and epithelia, which is important in organ morphogenesis, tumor progression, and cancer metastasis, and could represent a major event in the genesis of breast cancer.  We have developed and are utilizing various novel breast xenograft model systems by reconstituted chimeric breast tissue in which the stroma and epithelium are of distinct genetic make-up. This allows us to assess the mechanisms whereby Akt-specific isoforms function as critical regulators of epithelial and stromal homeostasis in healthy tissue as well as their contribution to tumor formation and progression. 4. The use of cells derived from genetically engineered mice to study the function of these genes in cell culture models. Our goal is to determine the various Akt family members’ functionality as target genes that modify signaling between stromal and epithelial cells during specific oncogene–induced mammary carcinogenesis events and their contribution to cancer progression and metastasis.