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    Determining the Role of CD44 in Breast Cancer Metastasis To the Lung

    Scientific Abstract:
    Scientific Abstract Title: Determining the role of CD44 in breast cancer metastasis to the lung Background: Metastatic invasion is the leading cause of breast cancer patient mortality, and a critical step in this process is the ability of transformed cells to migrate. The CD44 receptor can induce cellular adhesion and/or cellular migration, depending on cell specificity and ligand engagement. While some in vitro studies suggest that overexpression of CD44 or its ligands results in enhanced cellular motility, CD44-deficient (CD44-/-) mouse models demonstrate that the absence of CD44 can enhance tumor growth. To determine the physiological function of CD44 in tumor growth and metastasis, we have crossed the mouse mammary tumor virus-polyoma middle T antigen transgenic tumor model (MMTV-pyMT) onto a CD44-/- background. The absence of CD44 in this model resulted in a striking five-fold increase in pulmonary metastases when compared to CD44 heterozygous mice, while not affecting either primary tumor formation or growth rate. Furthermore, the expression of the matrix metalloproteinase, MMP9, dramatically increases in the pulmonary vasculature in CD44-/- mice bearing tumors. MMP9 is capable of degrading extracellular matrix, thereby supporting the growth of metastatic lesions. Hypothesis: We hypothesize that CD44 engagement suppresses metastatic invasion of transformed mammary gland epithelium by promoting adhesion to the stroma and by downregulating MMP9 expression. Specific Aims: (I) We will determine if CD44 engagement by HA at the epithelial/stromal interface inhibits the ability of the tumor to invade and inhibits MMP9 expression. (2) We will determine if CD44-mediated inhibition of metastasis formation is dependent upon the downregulation of MMP9 expression. Study Design: To investigate how CD44 expression is inhibiting tumor metastasis we will perform tumor explant migration assays into collagen gels cast with hyaluronan (HA – the primary ligand for CD44), and determine how this affects the ability of CD44-expressing (or CD44-ablated) breast cancer cells to invade. We will utilize invasion assays into mutant lung explants treated with MMP inhibitors to determine the effect of MMP9 activity on CD44-dependent invasion. Next, we will analyze CD44 and MMP9 double null mouse models, to determine how each factor is contributing to pulmonary metastasis in the MMTV-pyMT breast cancer model. By using a combination of genetically defined mouse models in the background of spontaneously developing breast cancer we are poised to identify the metastasis-promoting events of these signaling molecules in a physiological setting. Potential Outcomes and Benefits or the Research: CD44 has been widely reported as promoting transformation and invasion, but our data indicate it may play an important role in protection from metastasis. Clarification of the role of CD44 in tumor progression is vital if CD44-directed therapies are to be developed.

    Lay Abstract:
    Lay Abstract Title: Determining the role of CD44 in breast cancer metastasis to the lung Background: Progression to metastasis is the leading cause of breast cancer patient mortality, and a critical step in this process is the ability of cancer to survive and grow in distant organs. One protein highly produced by cancer is CD44, which can alternately cause cells to adhere or metastasize, depending upon the protein that activates it (ligand) and the cell type it is expressed on. Mouse models lacking CD44 production (CD44 null) demonstrate that the absence of CD44 can enhance tumor growth. To determine the physiological function of CD44 in tumor growth and metastasis, we have crossed a mouse breast cancer model (MMTV-pyMT) onto a CD44 null background. The absence of CD44 in this model resulted in a striking five-fold increase in lung metastases when compared to normal mice, while not affecting either tumor formation or growth in the breast. Interestingly, the expression of a tissue degrading enzyme, MMP9, dramatically increases in the lungs of CD44 null mice bearing tumors. MMP9 is capable of destroying tissue components thereby allowing tumor cells to move to new sites. Hypothesis: We hypothesize that CD44 engagement normally suppresses metastasis to the lung by inhibiting the release of proteins that allow tumors to spread. The lack of CD44 expression in our mouse model allows us to determine the contribution CD44 expression makes to breast cancer metastasis. Specific Aims: (1) We will determine if CD44 in the tumor cells in interacting with its ligands in the tissue and inhibiting the ability of tumors to metastasize. (2) We will determine if MMP9 expression is responsible for the observed increase in metastases in CD44 null mice by making genetic mouse crosses that also remove MMP9 production from our mouse models. Study Design: To investigate how CD44 expression is inhibiting tumor metastasis we will perform experiments with breast cancer cells in culture, and determine how activation of CD44 affects the ability of breast cancer cells to metastasize. To determine how CD44 is activated in the mouse models, we will determine where and how CD44 and its ligands are interacting in the tumors and metastases. Next, we will analyze CD44 and MMP9 mouse models to determine how each factor is contributing to lung metastasis in the MMTV-pyMT breast cancer model. By using models highly relevant to human breast cancer we are poised to identify how these proteins are involved in metastasis. Potential Outcomes and Benefits of the Research: CD44 has been widely reported as promoting transformation and invasion, but our data indicate it may play an important role in protection from metastasis. Clarification of the role of CD44 in tumor progression is vital if CD44-directed therapies are to be developed.