MAMMARY TUMOR CHEMOPREVENTION BY ANGIOGENIC INHIBITORS

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The goal of this research is to determine whether inhibitors of angiogenesis can serve as chemoprophylactics for breast cancer in high risk women. Our hypothesis is that: the genetic and epigenetic events which lead to pre-invasive breast disease also lead to an angiogenic phenotype; progression to advanced forms of pre-invasive breast disease is dependent upon angiogenesis; and blocking angiogenesis prevents the development of pre-invasive tumors, inhibits progression to the next stage and ultimately prevents invasive disease. For these studies we shall use two well-characterized models for the formation of pre-invasive and invasive mammary tumors, the 7,12-dimethylbenz[a]anthracene (DMBA) and N-nitroso-N-methylurea (NMU) - induced rat mammary tumors. Our specific aims are to investigate the time frame in which carcinogen-induced pre-invasive mammary tumors become angiogenic, that inhibition of angiogenesis prevents the formation and progression of carcinogen-induced pre-invasive and invasive breast tumors, that this occurs independent of the specific genetic or epigenetic pathway of carcinogenesis, and that inhibition of angiogenesis will potentiate the chemopreventive effects of estrogen receptor blocking agents. Two angiogenic inhibitors will be tested when given chronically, beginning at the time of carcinogen exposure, and after a one-month delay, to allow pre-invasive tumors to form prior to treatment. Tissues at different stages of tumor development will be examined for phenotypic changes such as histomorphology and degree of vascularity. In addition, they will be tested for angiogenic potential in angiogenic assays in vitro and in vivo. Finally, they will be examined for genetic changes, specifically the number and type of DNA-adducts and H-ras mutations at codon 61. This study is unique by examining the role of angiogenesis in pre-invasive tumors, an area that is largely unexplored. In addition, this study presents a non-hormonal approach to the problem of chemoprophylaxis in high-risk women.