100% of female transgenic mice expressing the polyoma middle T oncoprotein under control of the mouse mammary tumor virus promoter (MMTV-PyMT) develop multifocal mammary tumors. By several criteria, including tumor latency, growth rate, and metastasis, genetic ablation of the membrane-spanning NG2 proteoglycan greatly slows mammary tumor progression in the MMTV-FyMT model. Although NG2 is not expressed by mammary tumor cells in the MMTV-PyMT mouse, it is expressed by three important cell types in the tumor stroma: pericytes in the tumor microvasculature, adipocytes in the mammary fat pad, and macrophages that invade tumors from the circulation. We therefore hypothesize that effects of NG2 on vascularization, adipogenesis, and macrophage recruitment may affect mammary tumor progression by altering tumor cell interactions with these three key stromal elements.
The specific aims of this shortened ARRA version of the proposal will be to examine the respective effects of microvascular NG2 and macrophage NG2 on mammary tumor vascularization and progression in the MMTV-PyMT model.
In Aim 1, we will compare the tumor vascularization patterns seen in wild type and NG2 nulFrriice o? the MMTV-P7MT ba?kgroUnd. Thi'MTF i?ciudd?th Tnti?? dfV??UI?r fUhcf[oh (patency, basal lamina deposition, tissue hypoxia), morphology (tortuousity), and density, along with examination of pericyte/endothelial cell relationships leading to maturation of both cell types. We will also use Pdgfrb/Cre transgenic mice, in conjunction with a floxed NG2 allele, to generate a pericyte-specific NG2 null mouse. Mammary tumor progression in this mouse on the MMTV-PyMT background will more fully illuminate the pericyte-specific effects of NG2 on tumorigenesis.
In Aim 2 we will study the role of NG2 in macrophage-dependent tumor progression. This will include the recruitment of macrophages to developing tumors, and the role of macrophages in tumor vascularization, tumor cell intravasation, and tumor metastasis. We will also produce a macrophage-specific NG2 knockout mouse on the MMTV-PyMT background, using the lysozyme M/Cre mouse in conjunction with a floxed NG2 allele. This model will reveal macrophage-specific effects of NG2 on mammary tumor vascularization and progression
In spite of many improvements in detection and treatment, breast cancer continues to be one of the leading health risks for women, essentially putting victims at risk for the rest of their lives due to recurrence and metastasis of the disease to other organs. Improved treatment of breast cancer will require a deeper understanding of tumor-promoting factors associated with both the mammary tumor cells themselves and the environment in which the tumors reside. Our studies on the NG2 proteoglycan will enhance our understanding of a tumor-promoting molecule that is present in the tumor vasculature, the mammary fat pad, and tumor macrophages, thus potentially providing a multifocal target for breast cancer therapy.
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