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    Research Grants Awarded

    Loss of Syk as a prognostic marker in DCIS progression to invasive breast cancer

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background: Ductal carcinoma in situ (DCIS) is increasingly diagnosed in women through mammography . The progression from DCIS to invasive cancer is poorly understood. In some patients, DCIS does not progress into invasive breast cancer, whereas in other patients, DCIS may recur and develop into invasive and metastatic cancer. This uncertainty has prevented patients from choosing the most appropriate treatments. The spleen tyrosine kinase (Syk) is present in normal breast epithelial cells and is a promising candidate for a prognostic marker for DCIS. The mentor’s group first discovered that Syk was absent in invasive and metastatic breast cancer cells, and that transfection of Syk into breast cancer cells inhibited their invasion and metastases. Furthermore, Syk loss was seen in some but not all DCIS samples and may indicate poor outcomes for a subset of patients. Hypothesis/Objective: We hypothesize that loss of Syk is a marker for DCIS that will develop into invasive breast cancers. The objective of this study is to determine if Syk can be used to predict the outcome of DCIS. Specific Aims: 1) Determine if Syk expression is down regulated in cell line or xenograft models of DCIS. 2) Determine if Syk knockdown in Syk-positive breast epithelial cells with characteristics of normal, hyperplasia, DCIS will promote their transition to a more invasive or proliferative phenotype. 3) Determine if Syk expression levels are different in pure DCIS versus DCIS with adjacent invasive cancer. Study Design: To accomplish aim 1, we will use in situ hybridization, Western blotting, and immunohistochemistry to determine Syk levels in the MCF10 progression series of cell lines. We will find out if and when Syk is lost in these cells from normal to DCIS stages. To accomplish aim 2, we will use siRNA to decrease Syk levels in normal and malignant cells that contain Syk, and determine if this change promotes cell proliferation, invasion in vitro and tumor formation in vivo. To accomplish aim 3, we will use RT-PCR and immunohistochemistry to determine Syk levels in tissue sections of pure DCIS versus tissue sections of DCIS with adjacent invasive breast cancer. Relevance: The study proposed here will determine and validate Syk as a potential prognostic marker of DCIS, help us better understand the molecular events that occur during DCIS progression and facilitate clinical decision making in DCIS management.

    Lay Abstract:
    Background: Ductal carcinoma in situ (DCIS) is increasingly diagnosed in women through mammography . The progression from DCIS to invasive cancer is poorly understood. In some patients, DCIS does not progress into invasive breast cancer, whereas in other patients, DCIS may recur and develop into invasive and metastatic cancer. This uncertainty has prevented DCIS patients from choosing the most appropriate treatments. The spleen tyrosine kinase (Syk) is a protein molecule present in normal breast cells and is a promising candidate for a prognostic marker for DCIS. The mentor’s group first discovered that Syk molecules were absent in invasive and metastatic breast cancer cells, and that reintroducing Syk into breast cancer cells stopped their invasion and metastases. Furthermore, Syk loss was seen in some but not all DCIS samples and may indicate poor outcomes for a subset of patients. Hypothesis/Objective: We hypothesize that loss of Syk is a marker for DCIS that will develop into invasive breast cancers. The objective of this study is to determine if Syk can be used to predict the outcome of DCIS. Specific Aims: 1) Determine if Syk molecules are partially or completely lost in established cell line models of DCIS. 2) Determine if decreasing Syk levels in normal and DCIS cells will stimulate them to invade and metastasize. 3) Determine if Syk levels are different in patients with pure DCIS versus patients with both DCIS and adjacent invasive cancer. Study Design: To accomplish aim 1, we will use molecular biological and histopathological techniques to determine Syk levels in the MCF10 series of cell lines. We will find out if and when Syk is lost in these cells from normal to DCIS stages. To accomplish aim 2, we will use molecular biological techniques to decrease Syk levels in normal and DCIS cells that contain Syk, and measure if the cells’ abilities to invade, proliferate, and metastasize are enhanced. To accomplish aim 3, we will use molecular biological, histopathological and tissue microarray techniques to determine Syk levels in tissue sections of pure DCIS versus tissue sections of DCIS with adjacent invasive breast cancer. Relevance: The study proposed here will determine and validate Syk as a potential prognostic marker of DCIS, help us better understand the molecular events that occur during DCIS progression and facilitate clinical decision making in DCIS management.