GENETIC SUSCEPTIBILITY TO ESTROGEN INDUCED MAMMARY CA

对雌激素诱发的乳腺CA的遗传敏感性

• 批准号: 6497481
• 负责人: JAMES D SHULL
• 金额: $ 32.61万
• 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 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497481
• 关键词: breast neoplasms; carcinoma; disease /disorder etiology; disease /disorder model; estrogens; gene expression; genetic mapping; genetic strain; genetic susceptibility; hormone related neoplasm /cancer; laboratory rat; progesterone

DESCRIPTION: (adapted from the investigator's abstract) The investigators have recently demonstrated that ovary-intact, but not ovariectomized, female ACI rates treated continually with near physiologic levels of the naturally occurring estrogen, 17b-estradiol (ES2), rapidly develop multiple and often invasive mammary carcinomas. More recently, they have examined induction by E2 of mammary carcinoma in F1, F2 and backcross (BC) progeny of a genetic cross between females of t he highly susceptible ACI inbred strain and males of a resistant inbred strain, Copenhagen (COP). The data from this experiment closely fit models in which susceptibility to E2 -induced mammary cancers is conferred by the dominantly acting ACI allele of a single gene, referred to as EMCA-1 (Estrogen-induced Mammary Cancer-1) Moreover, it appears that the dominantly acting COP allele of an independently segregating gene, referred to as MCS-X (Mammary cancer suppressor-X), may act to delay development of mammary carcinomas in E2 treated progeny. These data provide the first evidence that susceptibility to E2 -induced mammary cancers in any species behaves as a relatively simple Mendelian trait conferred and/or modulated through the actions of limited number of genes. Because of the well documented role of estrogens in etiology of breast cancer in humans, the ACI rat appears to represent a unique and highly relevant animal model for the study of this disease. The hypotheses underlying the research proposed herein are: 1)EMCA-1 is necessary and sufficient to confer susceptibility to E2-induced mammary cancers; and, 2. MCS-X, segregating independently from EMCA-1 suppresses susceptibility to these E2 -induced mammary cancers. Herein they propose to map within the rat genome the locations at which EMCA-1 and MCS-X reside, and confirm the roles of these putative genes as modulators of susceptibility to E2- induced mammary cancers. j They will also define the role of progesterone in the etiology of E2-induced mammary cancer development in the ACI rat strain and further validate this strain as an important animal model for the study of breast cancer.

描述：（改编自研究者摘要） 研究人员最近证明，卵巢完整，但不 卵巢切除后，女性ACI率持续接受近 生理水平的天然雌激素，17 β-雌二醇 (ES2)迅速发展成多发性和经常是浸润性的乳腺癌。 最近，他们研究了E2对乳腺癌的诱导作用 在雌性之间遗传杂交F1、F2和回交（BC）后代中 高感ACI近交系和抗性ACI近交系的雄性 近交系，哥本哈根（COP）。 这个实验的数据 拟合模型，其中对E2诱导的乳腺癌的易感性是 由单个基因的显性作用ACI等位基因赋予， 作为EMCA-1（雌激素诱导的乳腺癌-1）此外，似乎 一个独立分离基因的显性COP等位基因 一种称为MCS-X（乳腺癌抑制因子-X）的基因可能起作用， 延迟乳腺癌在E2处理的后代中的发展。 这些 数据提供了第一个证据，即对E2诱导的 任何物种的乳腺癌都表现为相对简单的孟德尔式 通过有限数量的行为赋予和/或调节的特性 基因。 由于雌激素在病因学中的作用已被充分证实 在人类乳腺癌中，ACI大鼠似乎代表了一种独特的 和高度相关的动物模型，用于研究这种疾病。 的 本文提出的研究假设是：1）EMCA-1是 必要且充分地赋予对E2诱导的乳腺癌的易感性 癌症; 2。MCS-X，与EMCA-1独立分离，抑制 对这些E2诱导的乳腺癌的易感性。 在此，他们 建议在大鼠基因组中绘制EMCA-1和 MCS-X存在，并确认这些推定基因的作用， E2诱导的乳腺癌易感性的调节剂。J他们会 还定义了孕激素在E2诱导的 ACI大鼠品系中的乳腺癌发展，并进一步验证 该品系可作为乳腺癌研究的重要动物模型。