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    Research Grants Awarded

    Role of caveolin-1 and breast cancer mutants in epithelial transformation.

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background -- Loss of caveolin-1 (cav1) expression occurs in a subset of human cancers, and is associated with increased invasiveness of some epithelial cancer types. Mutation of cav1 is also associated with 35% of breast cancers in the United States. Caveolin proteins have a number of ascribed functions, yet the cellular consequence of loss or mutation of cav1 in multicellular situations is poorly understood. Objective/Hypothesis -- I will examine the function of cav1 during morphogenesis of the well-established 3-D canine kidney cell epithelial (MDCK) cyst model. Importantly, MDCK cysts will provide a model system to examine the function of cav1, and mutations thereof, in multicellular epithelial structures. Additionally, this system also inherently incorporates analysis of the influence of the extracellular matrix (ECM) in cellular phenotype, which is of emerging importance in cancer research. These studies will provide further mechanistic insight into the role of cav1 in epithelial cancer progression. Specific Aims -- I. Investigate the spatiotemporal expression of cav1 during epithelial cystogenesis and tubulogenesis. II. Explore the role of cav1 in epithelial morphogenesis/signaling using genetic silencing techniques. III. Characterize the effect of cav1 mutation (cancer-associated and phosphorylation-deficient mutants) on epithelial morphogenesis. Study Design -- These studies will use a combination of genetic silencing techniques and cell biological procedures to assess cav1 function in multicellular epithelial cysts and tubules. A range of cav1 antibodies (total, and phospho-specific) will be used to assess cav1 distribution during morphogenesis. shRNA viral technology will be used to silence cav1 expression to gauge loss of cav1 function in morphogenesis. This will be coupled to introduction of mutant cav1 alleles (phosphorylation-deficient forms, and alleles from human cancers), to further gauge the function of perturbed cav1 function in tumorigenesis. Moreover, the effect of cav1 perturbation on cellular signaling pathways will be assessed, and dissected using pharmacological inhibitors. The culture of MDCK cysts in ECM will inherently also analyze the contribution of ECM matrix to cav1 function. Potential Outcomes -- This work will provide mechanistic insight into the function of cav1 in multicellular epithelial structures, and will highlight pathways that are perturbed upon loss of this tumor suppressor. An immediate goal is to delineate which cellular structures and signaling pathways are affected by disruption of cav1. A longer-term goal is to provide insight into the contribution of cav1 perturbation in progression of human cancers.

    Lay Abstract:
    Background -- Loss of expression of the caveolin-1 gene (cav1) occurs in a subset of human cancers and is associated with increased invasion of some cancer types into surrounding tissues. Mutation of the cav1 occurs in 35% of breast cancers in the United States. Cav1 has a number of ascribed functions, yet the cellular consequence of loss of expression or mutation of cav1 in multicellular situations (e.g. in breast tissue, cysts or cancer) is poorly understood. Objective/Hypothesis -- I will examine the role of cav1 in the way cells function together as a tissue?like network using the well-established 3-D canine kidney cell epithelial (MDCK) cyst model. Importantly, MDCK cysts provide a model system to manipulate the function of cav1 in multicellular networks, a process difficult to do in whole animals. This system also uses advanced cell culture techniques that allow for analysis of the influence of extracellular matrix (ECM; proteins that naturally surround cells in the body) in the behavior of cells, which is of emerging importance in cancer research. These studies will provide crucial, fundamental insight into the role of cav1 in epithelial cancer progression. Specific Aims -- I. Investigate when/where cav1 is expressed in cells grown as cysts. II. Explore the role of cav1 in cyst behavior by genetically silencing cav1 expression. III. Characterize the effect of cav1 mutation (cancer-associated and other) on the behaviour of cells. Study Design -- These studies will use a combination of advanced genetic and cell biological procedures to assess cav1 function in cysts, a process developed in this laboratory. A range of commercial products (antibodies) will be used to assess when/where cav1 is expressed in cells. Genetic technology will be used to silence cav1 expression to gauge the consequence of loss of cav1 expression in cells. This will be coupled to introduction of mutant cav1 genes (found in some human cancers), to further gauge the function of perturbed cav1 in tumor-like alteration of cells. Commercial and common drugs will be used to analyze the consequence of cav1 disruption on known cancer-related cell pathways. The use of the cyst system proposed provides an important model to examine how cav1 functions in an organ-like situation ? a key advance towards understanding how cav1 and mutants influence cancer in the human body. Potential Outcomes -- This work will provide fundamental insight into the function of cav1, and its mutant forms, in cancer. An immediate goal is to uncover which cellular cancer-related pathways are affected by disruption of cav1. A longer-term goal is to understand how alteration of cav1 influences the progression of human cancers.