Identification and functional evaluation of proteins controlling proliferation and differentiation of mammary epithelial cells

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The mammary gland represents a uniquely suited model for the study of growth, differentiation and the control of organogenesis. We are planning to use mammary epithelial cells to identify the genes and to study the molecular mechanisms that govern their proliferation and differentiation. Since cancer formation is closely linked to aberrations of proliferation and differentiation programs, these results will also be most relevant for progress in breast cancer research. We have recently employed proteomics technology and identified new genes differentially regulated in the transition of mammary epithelial cells from a proliferation to a fully differentiated stage. These genes can be assigned to the control of RNA processing and stability, cytoskeletal organization and protein folding and stability. We now propose (1) to refine our approuch and analyse subcellular protein fractions with a new proteomics tool, (2) define the physiological funtion of interpretable candidate genes in a lactogenic hormone responsive cell culture model of mammary epithelial cells using lentiviral virus based knockdown technology and (3) verify out findings by transplantation and mammary gland reconstitution assays with genetically modified primary epithelial cells. These experiments represent a comprehensive analysis of crucial genes in mammary development and range from candidate gene identification to their functional evaluation in vitro and in vivo.