ROLE OF BGP IN BREAST EPITHELIAL CELL POLARIZATION

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The hallmark of epithelial cells is their polarized morphology and lumen formation. BGP (biliary glycoprotein), a type I transmembrane glycoprotein that is found throughout the gastrointestinal tract and other organs such as the breast, has a polarized expression on the lumenal surface of epithelial cells. We have shown that BGP plays an essential role in the lumen formation of the 'normal" breast epithelial cell line MCF10F when grown in matrigel, a source of extracellular matrix. Specifically, these cells fail to form a lumen (acinus) when BGP expression is blocked with a BGP anti-sense gene, or when the cells are treated with anti-BGP antibody or with recombinant, soluble BGP. In the case of breast tumor cell lines such as MCF7, which fail to form acini in matrigel and do not express BGP, these cells exhibit massive cell death and occasional acinus formation when transfected with the BGP sense gene and grown in matrigel. In order to delineate the molecular determinants of lumen formation by BGP, we propose to (1) study the defects in MCF7 cells which prevent their reversion to a more "normal" phenotype, (2) map cytoskeleton interactions with the cytoplasmic domain of BGP, (3) analyze the cis-trans dimer interactions of the BGP ectodomains responsible for lumen formation, and (4) determine the regulation of the BGP gene in both MCF10F and MCF7 cells. In addition, we have found that MCF10F cells produce myoepithelial cells which can be enriched and shown to be BGP negative and capable of induction of CEA (carcinoembryonic antigen), a hallmark of breast cancer cells. We will also study the regulation of the CEA and BGP genes in these cells in order to gain insight into the process of tumorigenesis in breast cancer.