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The SDF1-CXCR4 Axis In Breast Cancer Progression And Endocrine Resistance
Tumor Cell Biology II
Background : The primary long-term objective of this research is to understand how chemokine signaling influences progression of breast carcinoma cells to a hormone-independent and endocrine therapy resistant phenotype. While endocrine therapy holds great promise in treatment of hormone-dependent cancer, many tumors ultimately progress to a resistant phenotype. This resistance primarily occurs through altered cellular signaling cascades leading to ligand independent activation of estrogen receptor mediated gene expression and ultimately a hormone independent phenotype. Consistent with this, our preliminary evidence demonstrates that overexpression of Chemokine X receptor 4 (CXCR4) signaling in breast carcinoma cells leads to hormone independence in vivo. Objective/Hypothesis: We specifically hypothesize that altered expression of CXCR4 and activation by its ligand SDF1 directly controls progression to hormone independence in breast carcinoma cells through targeted regulation of estrogen receptor function. We further hypothesize that the SDF1-CXCR4 axis functions through G-protein coupled signaling through the downstream MAPK and PI3K-AKT pathways to promote progression to a metastatic and endocrine therapy resistant phenotype. Specific Aims: The following specific aims are proposed to determine the role and mechanisms of CXCR4 signaling in regulation of breast cancer progression to hormone independence and endocrine resistance. Specific Aim #1, to demonstrate CXCR4-G-protein signaling through MAPKs and AKT regulates ER-mediated gene expression. Specific Aim #2, to determine if CXCR4-estrogen receptor crosstalk regulates hormone-dependent and independent gene expression. Specific Aim #3, to implicate CXCR4-ER-mediated gene expression in the progression of cells to a hormone independent and endocrine resistant phenotype . Study Design: We use a combination of reporter gene assay and endogenous ER-responsive gene analysis to implicate a specific role for CXCR4-Gprotein-mediated signaling in the regulation of ER activity. We will validate a role for the CXCR4-ER signaling crosstalk and the generation of an autocrine feed-forward loop that mediates progression of breast carcinoma cells. We will further examine the role of CXCR4-ER crosstalk in the regulation of proliferation and cell survival of breast carcinoma cells.
Steroid hormones, particularly estrogen can influence the development and progression of breast cancer through specific receptors-estrogen receptors (ERs). While endocrine therapy represents a principle treatment for estrogen receptor (ER) positive breast carcinoma in the adjuvant and metastatic setting, many tumors ultimately progress to a resistant phenotype . The potential mechanisms for either intrinsic or acquired endocrine resistance are still poorly understood. The function of the ER-coregulated proteins and crosstalk with ER signal pathway, growth factor mediated signaling and other kinase networks may be involved in the molecular mechanisms responsible for the endocrine therapeutic resistance. Stromal derived factor-1 (SDF1) is a member of the CXC chemokine family identified as the unique ligand for CXCR4 receptor. The SDF1-CXCR4 axis has been implicated in the proliferation and survival of both normal and neoplastic cells. The role of SDF-1 CXCR4 in migration and homing has been extended to a metastasis of breast cancer . SDF1 is an estrogen target gene suggesting a link between chemokine signaling and hormonal responses, however the role of SDF1-CXCR4 in control of estrogen receptor signaling or hormone (estrogen)-dependent tumorigenesis has not been examined. Our results demonstrate that a CXCR4 positive phenotype drives breast cancer cells to a metastatic, hormone-independent and therapeutically resistant phenotype. In this grant we propose to understand the mechanism and role of the SDF1-CXCR4-ER axis in this progression. We will focus on identifying the signaling mechanisms by which CXCR4 activates the ER and leads to increased gene expression. Ultimately we will use a combination of pharmacological and molecular inhibitors of SDF1 or CXCR4 and downstream signaling pathways to attempt to override this hormone-independence and antiestrogen resistance. To be able to cure this disease we must understand the mechanisms and targets controlling breast cancer progression to a metastatic, resistant and ultimately fatal phenotype. The primary long-term objective of this research is to understand how chemokine signaling influences progression of breast carcinoma cells to an estrogen-independent and endocrine resistant phenotype and establish the chemokine axis as a therapeutic target in breast cancer progression .