ESTROGEN-DEPENDENT TUMOR GROWTH AND ANGIOGENESIS

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Estrogenic compounds play a critical role in cancer of the breast, uterus, and in some cases the liver, but the molecular sites of their action are not understood. A unique model of estrogen regulation of tumor growth and angiogenesis that has a firm genetic basis is the estrogen- induced growth of pituitary tumors in the Fischer 344 rat strain. These tumors display both increased growth and angiogenesis in response to either diethylstilbestrol or estradiol. We previously showed that the genetic basis for these estrogen-induced tumors is a small (2-4) number of genes. Recently, we genetically separated estrogen-dependent tumor growth and angiogenesis. Both traits are dependent upon multiple genes but neovascularization requires gene interaction (epistasis) for expression whereas overall growth is a simple additive trait. These findings compel us to attempt to map and clone the genes responsible for estrogen-dependent pituitary tumor formation in the F344 rat. Specifically, in our first aim, we will determine the linkage of tumor formation loci to molecular markers by quantitative trait interval mapping. To map tumor growth, we will use the traits of tumor mass and DNA content. To map genes for tumor angiogenesis, we will use the traits of hemorrhagic appearance and biochemical indicators of angiogenesis, such as hemoglobin content and CD31 levels. In our second aim, we will breed recombinant inbred lines of rats that contain tumor resistant genes from the Brown Norway strain in a genetic background from the Fischer strain. These new lines will be used to fine map these genes, leading to our third major aim; defining tumor growth and angiogenesis genes at the molecular level. We will map the genes with high resolution on the order of 1 centiMorgan.