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    Research Grants Awarded

    Amphiregulin and breast cancer metastasis to bone

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background: Nearly 70% of invasive breast cancers will produce metastasis to the bone. Parathyroid hormone-related protein (PTHrP) is an autocrine/paracrine factor produced by breast cancer cells that is speculated to play a major role in permitting breast cancer cells to grow in the bone microenvironment by stimulating the bone resorption axis. We have identified a potential role for amphiregulin in stimulating PTHrP gene expression in breast epithelial and cancer lines with the capacity to form osteolytic lesions. It has been previously shown that EGFR signaling induces the production of PTHrP in several primary and transformed epithelial cell types. We have since found that this signaling axis is present in breast cancer cells. Furthermore, we have also identified amphiregulin as the main ligand involved with the control of PTHrP in breast cancer cell lines. Objective/Hypothesis: Blockade of amphiregulin activation of the EGFR will reduce PTHrP signaling and inhibit cancer cell mediated destruction of bone in bone metastases. Specific Aims: Is soluble amphiregulin necessary for the osteolytic growth of breast cancer cells in the bone? Study Design: In this proposal, we set forth experiments to determine if amphiregulin is necessary for the growth of breast cancer in bone metastases. We propose to test in vitro and in vivo whether downregulation of amphiregulin influences the osteolytic potential of MDA and A1 breast cancer cell lines. These cell lines are able to form osteolytic lesions after cardiac injection into athymic nude mice. First, we will validate amphiregulin and the necessity of amphiregulin shedding as a target protein for breast cancer metastasis to bone using engineered cell lines. Second, we will treat mice bearing breast cancer metastases in the bone with a precipitating antibody to amphiregulin or a small molecule protease inhibitor, which are both in clinical trials for other diseases. Potential Outcomes and Benefits of the Research: Treatment of bone metastasis represents a tremendous challenge. This condition represents end stage of the disease and the cancer cells are likely to be resistant to many types of therapeutics. Given the large number of patients who will acquire this form of the disease, there is a great need for the development of many alternative therapeutic options for the treatment of this condition. Our findings will establish that amphiregulin is a useful target for the treatment of osteolytic breast cancer metastases. This will provide the basis of using existing therapeutics that target amphiregulin, as well as novel agents in subsequent clinical trials. This research is also an excellent stepping stone for beginning my independent research lab.

    Lay Abstract:
    In most cases cancer kills people by metastasis (traveling to distant sites) to vital organs and subsequent destruction of the tissue. This is the case for breast cancer patients as well. Metastasis is not entirely a random process. It turns out specific types of cancers frequently metastasize to certain locations. In the case of breast cancer, the vital organs that are most frequently associated with metastases tend to be bone, lung, brain and liver. The bone is the most common site of breast cancer metastasis, and virtually all patients who succumb to the disease will have metastasis to this site. The growth of cancer cells in the bone leads to bone loss, fractures and severe pain. Growth of breast cancer cells in any organ is very dangerous to the patient, but traditional therapies such as chemotherapy have been somewhat effective in shrinking tumors in the lung, liver and brain. Traditional therapies have not been very successful in slowing the growth of breast cancer cells in the bone. Recent progress in the field of osteoporosis has offered new insights into how tumor cells grow in bone and this work suggests novel avenues for the treatment of this devastating complication of breast cancer. The growth of breast cancer cells in bone is often dependent on stimulating the activity of the bone recycling process. Breast cancer cells make their own version of PTH (the hormone that regulates the bone recycling process) that is called parathyroid hormone related protein (PTHrP). When a metastatic breast cancer cell releases PTHrP in the bone, the net result is bone destruction and tumor growth without any new bone formation. This accounts for the bone loss, fractures and severe pain observed in patients whose breast cancer has metastasized to bone. This proposal is based upon the successful use of a FDA-approved drug that targets the production of PTHrP as well as its effects in normal bone cells in an animal model of breast cancer metastasis to bone. This drug is part of a group of recently developed therapeutics designed to target a receptor (called the epidermal growth factor receptor) that stimulates rapid cell division in many cancers, including some breast cancers. To this point, these compounds have not been effective in treating breast cancers. Some of our experimental findings suggests that part of the failure of these drugs may be related to the fact that the epidermal growth factor receptor works differently in cancer cells than predicted. The experiments contained in this proposal are designed to answer the following question: Can targeting the molecules that stimulate the epidermal growth factor receptor reduce the destruction of bone by metastatic breast cancer cells?