Genetic Susceptibility of Estrogen Induced Mammary CA

描述(申请人提供)：尽管许多流行病学、临床和实验室研究将雌激素与乳腺癌的病因学联系在一起，但雌激素促进乳腺癌发展的机制(S)仍然很大程度上仍不清楚。我们的实验室已经证明，ACI大鼠与大多数其他近交系大鼠不同，在持续使用自然产生的雌激素17β-雌二醇(E2)治疗时，它有患乳腺癌的独特倾向。雌激素治疗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)和无关的棕色挪威(BN)品系的乳腺癌发病率分别为20%和0%。在与COP和BN的杂交中，ACI表型以不完全显性和显性方式分离。我们已经定位了四个基因座，Emca1到Emca4，这至少在一定程度上赋予了这种独特的易感性。目的1鉴定一系列同源大鼠品系，其中携带ACI易感基因Emca1、Emca2和/或Emca3的等位基因已被耐药的COP或BN大鼠品系的等位基因所取代。我们假设：1)与ACI品系相比，在一个或多个Emca基因座携带COP或BN等位基因的大鼠对E2诱导的乳腺癌的易感性降低；以及2)每个Emca基因座可能选择性地影响不同的乳腺癌相关表型。目的2是建立和鉴定Emca4的同源大鼠品系。目标3是对每个Emca基因座进行精细定位，以更准确地确定导致和/或改变E2诱导乳腺癌易感性的基因的位置。目的4是确定EmCA基因座中的等位基因不平衡与雌激素诱导的乳腺癌发生之间的联系。需要检验的假设是，基因组中含有导致E2诱发乳腺癌的基因的区域，包括Emca基因座，将显示出等位基因失衡的速度高于整个基因组。目的5是在ACI来源的同源基因大鼠中检测E2诱导的乳腺癌发生，该同源基因大鼠患E2诱导的垂体肿瘤和相关的高催乳素血症的倾向显著降低。需要检验的假设是，E2诱导的乳腺癌发生和垂体肿瘤发生是独立的、在基因上可以分离的事件。本次更新申请中提出的研究将提供与雌激素和EmCA基因在乳腺癌病因学中的作用有关的机制信息，为鉴定这些乳腺癌易感基因提供基础，并进一步验证ACI大鼠是一种与人类乳腺癌高度相关的雌激素诱导乳腺癌发生的新模型。

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a series of congenic rat lines in which the susceptibility conferring ACI alleles of Emca1, Emca2 and/or Emca3 have been replaced by alleles from the resistant COP or BN rat strains.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.