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    Awarded Grants
    The Role of Chemokines and Their Receptors in Breast Cancer

    Scientific Abstract:
    The Role of Chemokines and Their Receptors in Breast Cancer Background: Chemokines are integral to physiologic processes such as organogenesis and inflammation; however recent studies have also focused on their roles in cancer. The “homing” theory describes how circulating molecules find tumor cells in a specific manner to promote invasion and metastases. Two chemokines and their respective receptors (CXCL12/CXCR4, CCL21/CCR7) have been implicated in this process in preclinical models of breast cancer. Thus far, large scale analyses on human cancers have not been performed. We propose utilization of immunohistochemistry (IHC) and tissue microarrays (TMA) for these studies. Conventional analysis however, suffers from discontinuous scoring, inherent subjectivity, and lack of reproducibility. We have developed a methodology called automated quantitative analysis (AQUA) that uses IHC on fixed tissue, but then employs molecular co-localization to quantify protein expression within sub-cellular compartments. Objectives/Hypothesis: We will correlate biomarker expressions on large cohorts of human breast cancers with clinico-pathologic endpoints. The underlying hypothesis is that a profile of these biomarkers as determined by TMA and AQUA analysis will help to i) predict likelihood of metastases and survival and ii) predict propensity to metastasize to specific sites in breast cancer. Specific Aims: 1.Use AQUA on a breast cancer TMA to correlate expression of CXCR4, CCR7, and their ligands with clinical endpoints. 2.Validate the prognostic significance of above biomarkers on a separate cohort of primary breast cancers with matched metastases. Study Design: A 650 patient TMA of breast cancer primaries with nodal metastases has been constructed from the Yale Pathology archives. Tumor samples will also be collected for the construction of a separate TMA of breast cancer primaries and matched recurrences. Complete pathologic, demographic and survival information will also be obtained. Antibodies will be titered to determine optimal signal to noise, then arrays stained for subsequent analysis with AQUA. Each array will be analyzed in conjunction with normal tissue and cell line controls. Potential Outcomes and Benefits of the Research: The potential impact of this proposal is two-fold. One is to begin clinical investigations of chemokines by assessing prognostic significance in breast cancer utilizing a novel software for in situ biomarker measurements. The second is to obtain preliminary data for the development of novel therapeutic targets in breast cancer.

    Lay Abstract:
    The Role of Chemokines and Their Receptors in Breast Cancer Background: Approximately 30% of patients with node negative breast cancer will suffer relapse. Modern therapies extend survival only modestly for those with metastatic disease and median survival remains under three years. These statistics highlight the need for i) more effective drugs in early stages to prevent relapse and in advanced stages to effect cure and ii) better prediction of long-term outcome. Chemokines and their receptors mediate movement of immune cells to sites of inflammation. Similarly, breast cancer preferentially spreads to certain sites including nodes, lung, and bone. The “homing” theory describes a process in which molecules (eg chemokines) are secreted into the circulation by certain organs (eg bone) to find their specific targets (eg chemokine receptors) on tumor cells to promote metastases. Two chemokines and respective receptors (CXCL12/CXCR4, CCL21/CCR7) have been implicated in this process in breast cancer models. We propose to study levels of these molecules on large numbers of human breast cancers using tissue microarrays (TMA) and a novel technology we have developed called automated quantitative analysis (AQUA) for protein assessment of TMAs. Objectives/Hypothesis: We will correlate the levels of above chemokines/receptors with outcome in breast cancer. The underlying hypothesis is that analysis of these biomarkers as determined by TMA and AQUA analysis, will help i) predict likelihood of metastases and survival and ii) predict propensity to metastasize to specific sites in breast cancer. Specific Aims: 1.Use AQUA on a breast cancer TMA to correlate expression of CXCL12/CXCR4 and CCL21/CCR7 with clinical endpoints. 2.Validate results on a separate group of breast cancers with matched metastases. Study Design: A TMA of 650 breast cancers has been constructed from Yale Pathology archives. Tissue will also be collected for a separate TMA of breast cancers with matched recurrences. Complete pathologic (eg size), demographic (eg age) and outcome (eg survival) information will also be obtained. The slides are stained with specific antibodies and analyzed with AQUA’s custom software. Potential Outcomes and Benefits of the Research: The potential impact of this proposal is two-fold. One is to study the prognostic ability of novel biomarkers in breast cancer utilizing a newly developed software for protein measurements in tissue. The second is to obtain preliminary data for the development of drugs targeted to chemokines and their receptors in breast cancer.