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    Research Grants Awarded

    Isolation of metastasis-inhibiting monoclonal antibodies

    Study Section:
    Detection, Diagnosis and Prognosis

    Scientific Abstract:
    Background: Most deaths resulting from breast cancer are due to subsequent metastases. While improvements in the diagnosis and screening of breast cancer have aided early detection of suspicious lesions, however, accurate prognosis of disease is as yet imprecise because of the unpredictable biology of breast cancer. Thus there is an urgent need to identify new molecular markers of breast cancer metastasis. Hypothesis: A proteomics approach can be used to discover metastasis related proteins in a breast tumor metastasis model. Specific Aims: Aim 1. Use subtractive immunization to isolate monoclonal antibodies (mAbs) which will specifically bind to the metastatic, monoclonal human breast tumor cell line, M4A4. Aim 2 . Perform in vitro assays in order to identify specific function-blocking monoclonal antibodies. Aim 3 . Evaluate the expression of antigens identified in Aims 1 & 2 in human breast tissue specimens. Study Design : Subtractive immunization will be performed using the isogenic, monoclonal human breast tumor cell lines NM2C5 (non-metastatic) and M4A4 (metastatic). Verification of candidate hybridoma products will be achieved by whole-cell ELISA analysis (antibodies must specifically recognize the metastatic cells). Next, in vitro assays will be employed in order to identify antibodies which can block the invasion/migration of a panel of breast cell lines. Antibodies that are proven to affect the invasive/metastatic behavior of the variant cell lines will be used to evaluate the expression of target antigens in archival human breast tissue specimens obtained from patients of known disease outcome. Potential outcomes and benefits of the research: It is the detection and eradication of metastases that presents the major clinical challenge of breast cancer. The unique combination of the proteomic techniques and our unique human breast tumor metastasis model, constitutes a powerful and innovative approach toward identifying proteins involved in the metastatic progression of breast cancer. The identification of specific metastasis-related breast tumor cell surface molecules, and/or ligands that bind to them, would be advantageous for several reasons: a) enabling the further analysis of the mechanism of metastasis, b) potential for improved detection and/or diagnosis of malignancy, and c) enable specific targeting of therapeutic agents.

    Lay Abstract:
    The disease of cancer is the result of inappropriate cell growth and division. The complex array of molecular interactions within a cell is normally tightly regulated in order to maintain the correct function of a specific cell type within its local environment. In cancer, accumulated genetic errors cause the tumor cell to lose its appropriate function and replicate out of control leading to the growth of a malignant tumor mass. However, it is the acquisition of the ability of tumor cells to spread to and affect distant organs (a process known as metastasis) which is the most clinically challenging. The major cause of breast cancer deaths result from the metastatic spread of the disease. In metastasis, the tumor cells continue to multiply at multiple sites, resulting in a geometric progression of tumor burden. The secondary tumors also tend to acquire drug-resistance, making it doubly difficult to eradicate. We hypothesize that there is a definitive pattern of changes in protein expression in tumor cells that are capable of metastatic spread. Novel techniques now available allow relatively large-scale screening of cell-surface proteins and it is therefore now feasible to compare the protein complement of cells with differing abilities to metastasize. We propose to apply these techniques to a pair of breast tumor cell lines that are derived from a single breast tumor source, but one of which has the propensity to spread from the breast to other organs in a mammalian host. The combination of the protein screening techniques and the unique series of increasingly metastatic breast cell lines constitutes a powerful and innovative approach toward identifying proteins involved in the metastatic progression of breast cancer. The technique initially isolates antibodies which will recognize metastasis-related proteins. These antibodies will have use as diagnostic and prognostic agents, but we will also identify the proteins that the antibodies recognize on the metastatic tumor cells. These proteins will be the subject of further long-term studies aimed at developing improved detection, imaging and therapeutic modalities.