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    Awarded Grants
    Regulation of the Preferential Skeletal Metastasis of Breast Cancers by Runx2

    Scientific Abstract:
    The studies proposed in this application are focused on elucidating the molecular mechanisms that regulate the interactions between tumor cells that seed bone (breast cancer metastases) and the bone environment. It is these reciprocal interactions that lead to the preferential establishment of metastases in bone and the diseases associated with skeletal metastases that result from cancer induced disruptions of the normal biological balance between bone formation and removal (remodeling). We have recently shown that metastatic breast cancer cells express the bone associated transcription factor Runx2. Our hypothesis is that Runx2 regulatory activity in breast cancer cells facilitates the reciprocal interactions between metastatic breast cancer cells and the bone microenvironment leading to the preferential establishment of skeletal metastases and the associated osteolytic destruction of bone. Our recently published experimental data demonstrates that disruption of Runx2 in breast cancer cells abolishes their ability to grow and generate osteolytic lesions when implanted at skeletal sites in vivo demonstrating a clear role for Runx2 in the interactions between breast cancer cells and the bone. In this application we propose two experimental aims both focused on the central role of Runx2 in the skeletal selective metastasis of breast cancers to bone. Aim one: This aim is designed to test the long held “seed and soil” theory proposed by Stephen Paget in 1889. These studies will directly test by in vivo implantation if breast cancer cells preferentially grow in bone as compared to other distant anatomical sites in vivo and determine if Runx2 activity is required for the preferential responses of breast cancer cells to the bone microenvironment. Aim two: - The second aim is based on the hypothesis that Runx2 is a central target of local bone morphogens (TGF-beta and BMPs) and is required for the cellular responses to the TGF-beta family of morphogens. In vitro cell culture systems will be used to directly analyze the role of Runx2 in mediating TGF-beta responses. The selective response to local bone morphogens is a major component of the preferential establishment of skeletal metastases and the associated skeletal diseases. These studies will provide a more thorough understanding of the basic molecular processes involved in the selective establishment of breast cancer metastases at skeletal sites and identify potential future therapeutic targets for the treatment and/or prevention of skeletal metastases.

    Lay Abstract:
    The studies proposed in this application are focused on understanding the molecular mechanisms that regulate the interactions between tumor cells that seed bone (breast cancer metastases) and the bone environment. It is these reciprocal interactions that lead to the preferential establishment of metastases in bone and the diseases associated with skeletal metastases. Our hypothesis is that metastatic breast cancer cells preferentially seed and grow in bone because they express a partial bone phenotype, referred to as osteomimicry, and this phenotype makes them preferentially responsive to the bone environment. Conceptually this is an attractive theory, what better way to integrate into a foreign site than by adopting the local cellular attributes. In support of this hypothesis, we have recently shown that metastatic breast cancer cells express a bone associated transcription factor called Runx2. Our recently published experimental data demonstrates that disruption of Runx2 in breast cancer cells abolishes their ability to grow and generate osteolytic lesions when implanted at skeletal sites in vivo demonstrating a clear role for Runx2 in the interactions between breast cancer cells and the bone. In this application we propose two experimental aims both focused on the central role of Runx2 in the skeletal selective metastasis of breast cancers to bone. The first aim will directly test if breast cancer cells preferentially grow in bone as compared to other distant anatomical sites in vivo in a Runx2 dependent manner. For these studies human breast cancer cell lines with and without Runx2 activity will be implanted in the bone, breast or under the skin in mice and analyzed for differences in cellular growth. The second aim is focused on identifying the mechanism by which Runx2 confers preferential responses of breast cancer cells to bone. Our hypothesis is that breast cancer cells grow preferentially in bone because of the unique growth factors stored in the bone and that Runx2 is required for breast cancer cells to respond to these local growth factors. Cell culture systems will be used to directly analyze the role of Runx2 in mediating breast cancer cell responses to the major bone associated growth factors, TGF-beta and bone morphogenic protein. Together these studies will provide a more thorough understanding of the basic molecular processes involved in the selective establishment of breast cancer metastases at skeletal sites and identify potential future therapeutic targets for the treatment and/or prevention of skeletal metastases.