ESTROGEN-DEPENDENT TUMOR GROWTH AND ANGIOGENESIS

雌激素化合物在乳腺癌中起关键作用， 子宫，在某些情况下还有肝脏，但它们的分子位点 行动不被理解。雌激素调节肿瘤的独特模型 生长和血管生成有一个坚实的遗传基础是雌激素， 在Fischer 344大鼠品系中诱导垂体瘤的生长。这些 肿瘤表现出增加的生长和血管生成， 己烯雌酚或雌二醇。我们以前表明， 这些雌激素诱导的肿瘤的遗传基础是一个小的（2-4）数字 基因。最近，我们从基因上分离了雌激素依赖性肿瘤 生长和血管生成。这两种特征都依赖于多个基因 但新血管形成需要基因相互作用（上位性）， 表达，而总体生长是简单的加性性状。这些 这些发现迫使我们试图绘制和克隆负责 F344大鼠雌激素依赖性垂体瘤形成。 具体地说，在我们的第一个目标中，我们将确定肿瘤 用数量性状区间将形成基因座与分子标记相结合 映射.为了绘制肿瘤生长图，我们将使用肿瘤质量的特征， DNA含量为了定位肿瘤血管生成的基因，我们将使用 出血外观和血管生成的生化指标， 例如血红蛋白含量和CD 31水平。在我们的第二个目标中，我们将 培育含有抗肿瘤基因的重组近交系大鼠 来自布朗挪威菌株的遗传背景来自费舍尔 株这些新品系将用于精细绘制这些基因， 我们的第三个主要目标是：在肿瘤生长和血管生成的基因中， 分子水平。我们将绘制高分辨率的基因图谱 1厘摩根

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.