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    Research Grants Awarded

    Syndecan-1 regulates {alpha}v{beta}3 integrin activity and signaling during mammary tumorigenesis

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Syndecan-1 (Sdc1) is coupled to the {alpha}v{beta}3 integrin (avb3) via a novel interaction of its core protein ectodomain and this association regulates avb3 activity in mammary carcinoma and endothelial cells. I have shown that Sdc1 ectodomain (S1ED) protein, peptides or antibodies (treatments which competitively displace avb3 away from native Sdc1) and siRNA-mediated silencing of Sdc1 blocks avb3 integrin activity thus disrupting avb3-dependent mammary carcinoma cell adhesion, spreading and migration in vitro. The aim of this project is to examine whether this Sdc1-avb3 regulatory mechanism characterized in vitro plays a role in tumorigenesis in vivo, either on tumor cells, where the integrin plays an important role in tumor invasion and metastasis or in the stromal compartment, including the vasculature where this integrin has been shown to be important for angiogenesis. I propose two experimental schemes. The first approach entails putting MDA-MB-435 human mammary carcinoma cells, cells in which the syndecan regulatory mechanism was first described, into SCID mice. Cells lacking Sdc1 (via siRNA-mediated silencing), but expressing avb3 integrin, will be transfected to express Sdc1 ectodomain mutants that can or cannot activate the integrin and then injected into a cleared mammary fat pad or lateral tail vein of female SCID mice. This will examine the impact of the Sdc1-avb3 regulatory mechanism on tumor formation/invasion and metastasis, respectively. An avb3 integrin inhibitory peptide that represents the Sdc1 ectodomain active site will also be tested as an anti-tumorigenic therapeutic. The second approach examines the relevance of the Sdc1-avb3 regulatory mechanism using an established mouse mammary tumor model that closely parallels progression of the human disease. Mice expressing the polyomavirus middle T oncogene under transcriptional control of the mouse mammary tumor virus promoter/enhancer (MMTV-PyMT) will be crossed with Sdc1+/- mice to produce animals with mammary tumors in which the Sdc1- avb3 regulatory mechanism is either active (Sdc1+/+) or inactive (Sdc1-/-). Comparing these animals, I can examine whether the absence of this mechanims (due to a lack of Sdc1) has any effect on mammary tumor formation, invasion and metastasis induced by the PyMT transgene relative to Sdc1+/+ cells where the mechanism is active. If the loss of Sdc1 translates to a deleterious effect on the tumors, then I will test whether expression of Sdc1 in Sdc1-/-cells rescues tumor formation, invasion and/or metastasis. Finally, I propose to isolate Sdc1+/+ and null tumor cells and introduce them into Sdc1-/- and Sdc1+/+ mice, backgrounds in which the Sdc1-avb3 regulatory mechanism is absent and present, respectively. This will allow me to examine the relevance of the Sdc1-avb3 regulatory mechanism in tumor cells vs. the stromal compartment and whether circulating S1ED inhibitory peptide affects tumorigenesis by acting on the tumor or stroma.

    Lay Abstract:
    This project aims to study whether syndecan-1 (Sdc1), a protein robustly expressed within the breast, promotes breast cancer via its interaction with and regulation of the {alpha}v{beta}3 integrin, a protein already known to contribute to breast cancer growth, survival and spread in humans. This project will examine when (i.e., early vs. later stages of breast cancer) and where (i.e., within breast tumor cells themselves or in cells that surround the tumors) these two proteins, together, act to contribute to breast cancer progression. This will be done using established mouse breast tumor models that closely mimic the progression of the disease in humans. Using these mouse models, I will test whether loss of Sdc1 within the breast (either through genetic deletion or by treatments that block expression of the protein), blocks {alpha}v{beta}3 integrin-dependent breast cancer growth and spread within the body. Further, upon completion of these studies, I will have identified whether Sdc1 protein fragments, which have been shown to act as {alpha}v{beta}3 integrin inhibitors, can be potentially used as an anti-breast cancer therapeutic.