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The overall goal of this project is to determine if human breast cancer can be prevented from becoming angiogenic when it is still at a microscopic size (i.e., < 1 cubic millimeter). During the past year, from February 2005 to February 2006, the authors cloned three different human breast cancers that undergo the angiogenic switch at predictable times. They found that the angiogenic switch time is modified by host stroma; it is two-fold earlier for tumors in the mammary fat pad compared to tumors implanted in subcutaneous tissue. They also found that the angiogenic switch is preceded by repression of stromal expression of thrombospondin-1. Angiogenic tumor cells continue to secrete a novel thrombospondin-1 repressing factor. This protein has been purified and partially sequenced. For one of the breast cancers, the angiogenic switch can be detected when the tumor is microscopic in size by a significant increase in bFGF in platelet alpha granules. They also determined that the BRCA1 gene (breast cancer susceptibility gene), appears to regulate a ratio of thrombospondin-1 to VEGF in breast cancer cells. The lower the thrombospondin-1/VEGF ratio, the sooner the tumor cells will spontaneously switch to the angiogenic phenotype and grow large tumors in SCID mice. The article, 'A Model of Human Tumor Dormancy: An Angiogenic Switch from the Nonangiogenic Phenotype' by George N. Naumov, et al. is appended.