Genetic Susceptibility of Estrogen Induced Mammary CA

描述（由申请人提供）：尽管大量的流行病学、临床和实验室研究将雌激素与乳腺癌的病因不可避免地联系在一起，但雌激素促进乳腺癌发展的机制在很大程度上仍然未知。我们的实验室已经证明，ACI大鼠在持续使用天然雌激素17 -雌二醇（E2）治疗时，其发展为乳腺癌的独特倾向与大多数其他近交系大鼠不同。E2治疗28周后，雌性ACI大鼠的乳腺癌发病率几乎为100%，而基因相关的哥本哈根（COP）和非基因相关的布朗挪威（BN）菌株的发病率分别为20%和0%。在与COP和BN杂交中，ACI表型分化为不完全显性和显性。我们已经绘制了四个基因座，Emca1到4，它们至少部分地赋予了这种独特的易感性。目的1是表征一系列遗传大鼠系，其中Emca1、Emca2和/或Emca3的ACI易感性等位基因被耐药的COP或BN大鼠菌株的等位基因所取代。我们假设：1)在一个或多个Emca基因位点携带COP或BN等位基因的大鼠对e2诱导的乳腺癌的易感性较ACI菌株低；2)每个Emca位点可能选择性地影响不同的乳腺癌相关表型。目的2是开发和表征Emca4基因大鼠系。目的3是绘制每个Emca位点的精细图谱，以更精确地确定赋予和/或改变e2诱导乳腺癌易感性的基因位置。目的4是确定Emca基因座内的等位基因失衡与e2诱导的乳腺癌发生之间的关系。待验证的假设是，基因组中含有e2诱导乳腺癌基因的区域，包括Emca基因座，将以高于整个基因组的速度表现出等位基因失衡。目的5是在aci衍生的先天性大鼠系中检测e2诱导的乳腺癌发生，该系显示e2诱导的垂体肿瘤和相关的高泌乳素血症的倾向显著降低。要验证的假设是e2诱导的乳腺癌发生和垂体肿瘤发生是独立的和基因上可分离的事件。本次更新申请的研究将提供雌激素和Emca基因座在乳腺癌病因学中的作用机制信息，为确定这些乳腺癌易感基因提供基础，并进一步验证ACI大鼠作为e2诱导的与人类乳腺癌高度相关的新型乳腺癌模型。

DESCRIPTION (provided by applicant): Although numerous epidemiologic, clinical and laboratory studies inextricably link estrogens to the etiology of breast cancer, the mechanism(s) through which estrogens contribute to breast cancer development remain largely unknown. Our laboratory has demonstrated that the ACI rat is unique from most other inbred rat strains in its unique propensity to develop mammary carcinoma when treated continuously with the naturally occurring estrogen, 17beta-estradiol (E2). Whereas mammary cancer incidence following 28 weeks of E2 treatment is virtually 100% in female ACI rats, incidence in the genetically related Copenhagen (COP) and unrelated Brown Norway (BN) strains is 20% and 0% respectively. The ACI phenotype segregates in an incompletely dominant and dominant manner in crosses to COP and BN. We have mapped four loci, Emca1 through 4, which confer, at least in part, this unique susceptibility. Aim 1 is to characterize a series of congenic rat lines in which the susceptibility conferring ACI alleles of Emca1, Emca2 and/or Emca3 have been replaced by alleles from the resistant COP or BN rat strains. We hypothesize that: 1) rats carrying COP or BN alleles at one or more of the Emca loci will exhibit reduced susceptibility to E2-induced mammary cancer, relative to the ACI strain; and 2) each Emca locus may selectively impact different mammary cancer associated phenotypes. Aim 2 is to develop and characterize a congenic rat line for Emca4. Aim 3 is to fine map each Emca locus to establish more precisely the locations of the genes that confer and/or modify susceptibility to E2-induced mammary cancer. Aim 4 is to define the association between allelic imbalances within the Emca loci and E2-induced mammary carcinogenesis. The hypothesis to be tested is that regions of the genome harboring genes that contribute to E2-induced mammary cancer, including the Emca loci, will exhibit allelic imbalances at a rate above that of the genome at large. Aim 5 is to examine E2-induced mammary carcinogenesis in an ACI-derived congenic rat line that exhibits a significantly reduced propensity to develop E2-induced pituitary tumors and associated hyperprolactinemia. The hypothesis to be tested is that E2-induced mammary carcinogenesis and pituitary tumorigenesis are independent and genetically separable events. The studies proposed in this renewal application will provide mechanistic information relating to the roles of estrogens and the Emca loci in mammary cancer etiology, provide the foundation for efforts to identify these mammary cancer susceptibility genes and further validate the ACI rat as a novel model of E2-induced mammary carcinogenesis that is highly relevant to human breast cancer.