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    Research Grants Awarded

    Regulation of novel cytoskeletal protein complexes involved in breast cancer initiation and progression

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    Background: One of the hallmarks of cellular transformation is gross alterations in cytoskeletal architecture leading to increased cellular motility and the invasive behavior that will ultimately contribute to the onset of metastatic disease. The formation of unique actin based structures called podosomes and invadopodia provide a marker for the onset of this phenotypic switch. Invadopodia are unique membrane protrusions that exhibit extracellular matrix degrading activity. Although the function of these structures has been identified, their regulation and the stimuli that cause their formation and activity remain almost completely undiscovered. Objective/ Hypothesis: We hypothesize that actin reorganization in response to transformation results in unique intermolecular associations. Formation of unique protein complexes will have functional consequences upon cell behavior. We propose that a subset of these complexes regulate the formation and activity of podosomes and invadopodia. This proposal will undertake a comprehensive examination of the regulation and formation of these cellular structures and how this regulation affects their function and activity. Specific Aims: These will include a study of the formation and regulation of invadopodia-associated complexes in MDA-MB-231 breast cancer cells , a study of the formation and regulation of cortactin containing adhesion and motility related complexes in MCF-7 breast cancer cells and a focus on the role of paxillin and PKD1 in breast cancer cell invasion and metastasis. Study Design: This study will use a coordinated study design using biochemical, molecular and microscopy based approaches to examine the formation and regulation of invasion and motility associated protein complexes. Potential Outcomes and Benefits of the research: We anticipate that these studies will identify critical points in the phenotypic shift of a tumor cell as it acquires motile and invasive characteristics. The identification of key proteins associated with that shift and the intermolecular associations that these proteins participate in and or regulate will provide new pathological markers for recognizing breast cancer progression. Further, these pathways and the proteins that regulate them will also be targets for novel therapeutic approaches.

    Lay Abstract:
    Background: The phenotypic transformation of a normal breast epithelial cell to that of a tumor cell requires a profound reorganization of its structural components. This rearrangement is centered on regulation of the actin cytoskeleton and the processes that bring these changes about. It has been observed that a key alteration is the formation of actin-containing subcellular structures termed podosomes or invadopodia. These structures lie at, what is hypothesized to be, the leading edge of an invasive cell, existing only where the cell is in direct contact with the matrix that it will subsequently degrade. Objective/ Hypothesis: That there are mechanisms required for invadopodia formation and activity that can be identified. Further, a study of these pathways and their regulation may allow identification of potential diagnostic markers for breast cancer progression from non-invasive to invasive and metastatic disease. Finally, these pathways may also represent therapeutic targets for breast cancer progression. Specific Aims: These will include a study of the formation and regulation of invadopodia complexes in MDA-MB-231 breast cancer cells , a study of the formation and regulation of cortactin containing adhesion and motility related complexes in MCF-7 breast cancer cells and a focus on the role of paxillin and PKD1 in breast cancer cell invasion and metastasis. Study Design: This study will use a coordinated study design using biochemical, molecular and microscopy based approaches to examine the formation and regulation of invasion and motility associated protein complexes. Potential Outcomes and Benefits of the research: We anticipate that these studies will identify critical points in the phenotypic shift of a tumor cell as it acquires motile and invasive characteristics. The identification of key proteins associated with that shift and the intermolecular associations that these proteins participate in, and or regulate, will provide new pathological markers for recognizing breast cancer progression. Further, these pathways and the proteins that regulate them will also be targets for novel therapeutic approaches.