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    Awarded Grants
    Regulation of Breast Cancer Metastasis by Slit

    Scientific Abstract:
    Project Title: Regulation of Breast Cancer Metastasis by Slit Background: The main cause of death in patients with breast cancer is its metastasis to organs such as the bones, lungs, and lymph nodes. Recently, it was shown that the chemokine receptor CXCR4 is highly expressed in breast cancer cells and that its ligand, CXCL12, is expressed by organs that are sites for metastasis. It was also shown that the CXCR4/CXCL12 axis mediates homing of these cancer cells to these organs. We are developing innovative strategies to block the chemokine-mediated metastasis of breast cancer cells. In this regard, we have shown that a novel biological molecule, Slit, blocks CXCL12-induced chemotaxis, chemoinvasion, and adhesion, the fundamental components that promote the metastasis of breast cancer cells. Slit binds to a repulsive guidance transmembrane receptor known as the roundabout (Robo) receptor. Slit and Robo were initially identified in brain and were shown to regulate and block neuronal migration. We have shown that breast cancer cells derived from patients express the Robo receptors. Furthermore, analysis of Slit-mediated anti-chemotactic signaling mechanisms revealed down-modulation of the activities of related adhesion focal tyrosine kinase (RAFTK), beta-catenin, and metalloproteinases. Objective/Hypothesis: The main objective of this project is to analyze the role of Slit as an anti-metastatic factor in breast cancer cells. We hypothesize that 1) Slit treatment will inhibit breast cancer metastasis to lungs and lymph nodes; 2) Slit induces cross-talk between Robo and chemokine receptors; and 3) Slit inhibits metalloproteinase secretion by blocking function of RAFTK and b-catenin. Study Design: To test these hypotheses, we will analyze the regulatory region within Slit that mediates anti-metastatic functions. In aim 1, we will study the effects of different truncated Slit molecules on the chemoinvasion/chemotactic/adhesive properties of various breast cancer cells. After in vitro characterization, we will study in vivo effects of Slit and its truncated forms on the pathogenesis of breast cancer metastasis in a mouse model system. In aim 2, we will define the domain on the cytoplasmic tail of the Robo receptors that interacts with the chemokine receptor, CXCR4. We will also study the effect of the truncated form of the Robo receptor on breast cancer metastasis. In aim 3, we will define the role of RAFTK, N-cadherin, and b-catenin in Slit-mediated anti-chemotactic chemoinvasion mechanisms by using various pharmacological inhibitors and dominant negative mutants of these molecules. Potential Outcome and Benefits of Research: Innovative therapeutic strategies to prevent breast cancer metastasis can be anticipated based upon blocking the chemokine-induced chemotaxis/chemoinvasion and adhesion of breast cancer cells. In addition, Slit could be used as a single upstream target for metastasis induced by various chemokines. These studies will help us to identify Slit-mediated anti-chemotactic/chemoinvasive pathways that may become novel targets for the treatment of breast cancer metastasis.

    Lay Abstract:
    Project Title: Regulation of Breast Cancer Metastasis by Slit Breast cancer, when detected at an early stage, is highly treatable and often curable by surgery, radiation, chemo and/or hormone therapies. However, the major cause of increased morbidity and eventual mortality in breast cancer patients is metastasis. The development of breast cancer metastasis involves enhanced adhesion, passage through cell walls, and the migration of breast cancer cells to target organs such as the lungs, lymph nodes, and bone. Our laboratory is investigating the role of the novel protein Slit and its receptor, Robo, in inhibiting breast cancer metastasis. We have shown that Slit blocks CXCL12-induced breast cancer cell movement as well as its adhesive and invasive properties. The chemokine CXCL12 mediates its action through the chemokine receptor CXCR4, which is more highly expressed in breast cancer tumors than in normal breast tissues. Furthermore, it was shown that the target organs of beast cancer metastases produce CXCL12. We hypothesize that the Slit/Robo-mediated inhibition of CXCR4/CXCL12 and other chemokines would block breast cancer cells from metastasizing to the bone, lungs, and lymph nodes. To test this hypothesis, we will analyze the effect of Slit on the pathogenesis of breast cancer metastasis in a mouse model system. We will also define the region in the Slit molecule that possesses anti-metastatic properties. We have shown that Slit mediates its effects by blocking the function of structural components that enhance cell movement and the expression of metalloproteinases, which promote the invasive properties of breast cancer cells. We will further delineate the Slit-induced intracellular signaling pathways that block cytoskeletal changes and expression of metalloproteinases in breast cancer cells. These signaling molecules could be used as drug targets for inhibiting breast cancer metastasis. Our studies suggest that Slit, which inhibits breast cancer cell movement and invasion, has the potential to prevent the development of breast cancer metastasis and thus reduce mortality in breast cancer patients. Understanding of Slit-mediated signaling pathways will aid in the development of new and targeted strategies against breast cancer metastasis.