) Tumor progression and metastasis of breast cancer is directly dependent on blood vessel formation. By understanding the mechanisms that control the neovascular response, it may be possible to design therapeutic strategies to selectively prevent or halt pathological growth of vessels and consequently restrain the progression of cancer cells. Present therapeutic approaches for breast cancer have generally excluded target ablation of neovascular growth; mostly because we lack information on the specific properties and genetic make-up of the endothelium present in the normal and/or pathologic mammary gland. Identification of genes uniquely expressed in mammary gland endothelial cells is essential for the development of vascular targeting therapy. The applicant has isolated mouse mammary gland endothelial cells. The preliminary studies have identified specific differences in secreted proteins when mammary endothelial cells are compared to microvascular endothelial cells from other organs. These results suggest that endothelial cells from mammary tissue have a particular pattern of gene expression not shared by other vascular endothelium. Also the results indicated that mammary gland endothelial cells express and respond to steroid hormones. Also a feature not described in many other types of endothelium. Although various aspects of physiology, endocrinology, and mechanisms of action of steroid hormones have been well studied, the biology of endothelial cells in relation to steroid hormones in normal and tumor tissue has received very little attention, a concerning fact considering their broad applicability in contraception and in tumor therapy. Experiments outlined in this application have been designed to provide a comprehensive characterization of mammary gland endothelial cells and to identify, at the molecular level, specific differences between these cells and endothelial cells from other capillary beds. The applicant plans to capitalize on the previous observations that endothelial cells of mammary gland origin respond to reproductive hormones and pay particular attention to the effect of estrogen and progesterone in these cells. The regulation and characterization of endothelial cell function in the mammary gland is an unexplored and potentially important avenue that could have broad implications for the clinical management of breast cancer.
| Graubert, M D; Ortega, M A; Kessel, B et al. (2001) Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1. Am J Pathol 158:1399-410 |
| Iruela-Arispe, M L; Rodriguez-Manzaneque, J C; Abu-Jawdeh, G (1999) Endometrial endothelial cells express estrogen and progesterone receptors and exhibit a tissue specific response to angiogenic growth factors. Microcirculation 6:127-40 |
| Vazquez, F; Rodriguez-Manzaneque, J C; Lydon, J P et al. (1999) Progesterone regulates proliferation of endothelial cells. J Biol Chem 274:2185-92 |
