Genetic Susceptibility of Estrogen Induced Mammary CA

雌激素诱发乳腺CA的遗传易感性

• 批准号: 6845263
• 负责人: JAMES D SHULL
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845263
• 关键词: biological signal transduction; breast neoplasms; disease /disorder etiology; estrogens; flow cytometry; gene expression; genetic mapping; genetic strain; genetic susceptibility; hormone related neoplasm /cancer; immunocytochemistry; inbreeding; laboratory rat; pituitary neoplasms; polymerase chain reaction; progesterone receptors; prolactin

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a series of congenic rat lines in which the susceptibility conferring ACI alleles of Emca1, Emca2 and/or Emca3 have been replaced by alleles from the resistant COP or BN rat strains.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

描述（由申请人提供）：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在很大程度上仍然未知。我们的实验室已经证明，ACI大鼠是独特的，从大多数其他近交系大鼠品系在其独特的倾向，发展乳腺癌时，连续与天然存在的雌激素，17 β-雌二醇（E2）。而乳腺癌的发病率后28周的E2治疗几乎是100%的雌性ACI大鼠，发病率在遗传相关的哥本哈根（COP）和无关的布朗挪威（BN）株分别为20%和0%。ACI表型在与COP和BN的杂交中以不完全显性和显性方式分离。我们已经绘制了四个位点，Emca 1至4，这赋予，至少部分，这种独特的易感性。目的1是表征一系列同源大鼠品系，其中赋予ACI易感性的Emca 1、Emca 2和/或Emca 3等位基因已被来自抗性COP或BN大鼠品系的等位基因所取代。我们假设：1）相对于ACI品系，在一个或多个Emca基因座处携带COP或BN等位基因的大鼠将表现出对E2诱导的乳腺癌的易感性降低;以及2）每个Emca基因座可以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Emca 4的同类大鼠系。目的3是精细定位每个Emca基因座，以更精确地确定赋予和/或改变E2诱导的乳腺癌易感性的基因的位置。目的4是确定Emca基因座内等位基因失衡与E2诱导的乳腺癌发生之间的关联。要测试的假设是，基因组的区域窝藏的基因，有助于E2诱导的乳腺癌，包括Emca基因座，将表现出等位基因的不平衡率高于整个基因组。目的5是研究E2诱导的乳腺癌发生在ACI衍生的同类大鼠系，表现出显着降低的倾向，发展E2诱导的垂体瘤和相关的高泌乳素血症。有待检验的假设是，E2诱导的乳腺癌和垂体肿瘤是独立的和遗传上可分离的事件。本次更新申请中提出的研究将提供与雌激素和Emca基因座在乳腺癌病因学中的作用相关的机制信息，为鉴定这些乳腺癌易感基因的工作提供基础，并进一步验证ACI大鼠作为E2诱导的乳腺癌发生的新型模型，该模型与人类乳腺癌高度相关。