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: 6412740
• 负责人: JAMES D SHULL
• 金额: $ 7.55万
• 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 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6412740
• 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：(改编自调查人员的摘要) 研究人员最近证明，卵巢是完整的，但不是 卵巢切除，女性ACI发生率持续用NEAR治疗 自然产生的雌激素--17b-雌二醇的生理水平 (ES2)，迅速发展为多发性且常为浸润性的乳腺癌。 最近，他们研究了雌激素对乳腺癌的诱导作用。 雌性间遗传杂交的F1、F2和回交(BC)后代 对ACI高度敏感的近交系和抗病雄性 近交系，哥本哈根(COP)。这项实验的数据非常接近 E_2诱发乳腺癌易感性的拟合模型 由单基因的显性作用的ACI等位基因赋予的，指 作为EMCA-1(雌激素诱导的乳腺癌-1)，而且，它似乎 独立分离的主要作用COP等位基因 基因，被称为MCS-X(乳腺癌抑制基因-X)，可能起作用 雌激素治疗子代乳腺癌的延缓发展。这些 数据提供了第一个证据，即对E2的易感性 任何种类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。因为雌激素在病因学中的作用已得到充分证实 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来研究这种疾病。这个 本文提出的研究假设是：1)EMCA-1是 使人对雌激素性乳房易感性的充要条件 癌症；以及，2.MCS-X，独立于EMCA-1，抑制 对这些雌激素性乳腺癌的易感性。在这里，他们 建议在大鼠基因组内绘制EMCA-1和EMCA-1 MCS-X驻留，并确认这些假定基因的作用为 雌激素诱发乳腺癌的易感性调节因子。J他们会的 同时明确孕酮在雌激素性激素诱导的病因中的作用 ACI大鼠株系乳腺癌的发生发展及进一步验证 该菌株可作为研究乳腺癌的重要动物模型。