2-METHOXYESTRADIOL & HORMONAL CANCER

描述（申请人提供）：2-甲氧基雌二醇（2-MeO-E2）是一种非极性内源性雌激素代谢物，由2-羟基雌二醇（人类最丰富的羟基雌激素代谢物）代谢O-甲基化形成。 2-MeO-E2 在非生理性高浓度下具有抗增殖、细胞凋亡和抗血管生成作用。该拨款申请有两个总体目标：(i) 通过在人类乳腺癌细胞系中寻找 2-MeO-E2 的特定细胞受体来研究 2-MeO-E2 作用的分子机制。我们将分离人类乳腺癌细胞中存在的 2-MeO-E2 的特异性、高亲和力细胞受体，并确定其蛋白质和 DNA 序列（在具体目标 1 下描述）。 (ii) 确定内源形成或外源施用的 2-MeO-E2（在生理相关浓度）是否对常用动物模型中雌激素诱导的乳腺肿瘤形成具有化学保护作用。我们将确定外源性施用的 2-MeO-E2 对雌性 ACI 大鼠中雌二醇诱导的乳腺肿瘤发生的保护作用，并且我们还将通过确定长期施用恩他卡朋（一种选择性 COMT 抑制剂）是否会改变雌性 ACI 大鼠中雌二醇诱导的乳腺癌发生来评估内源性形成的 2-MeO-E2 的乳腺癌保护作用。这些研究在具体目标 2、3 和 4 下进行了描述。我们提出的研究预计将增进我们对 2-MeO-E2（一种在人类中大量形成的非极性内源性雌激素代谢物）的乳腺癌保护作用的了解。这些知识将为未来开发预防人类乳腺癌的新方法奠定基础，通过施用“生理剂量”的 2-MeO-E2（或其合成类似物），或使用可以以有益的方式改变内源性 2-MeO-E2 的代谢形成和/或处置的药物。该结果还将为 2-MeO-E2 的生物作用提供新的机制理解。

DESCRIPTION (provided by applicant): 2-Methoxyestradiol (2-MeO-E2) is a nonpolar endogenous estrogen metabolite formed by metabolic O-methylation of 2-hydroxyestradiol (the most abundant hydroxyestrogen metabolite in humans). 2-MeO-E2 has anti-proliferative, apoptotic, and antiangiogenic actions at nonphysiological high concentrations. This grant application has two overall goals: (i) to study the molecular mechanism(s) of 2-MeO-E2's action by searching for its specific cellular receptor in human breast cancer cell lines. We will isolate a specific, high-affinity cellular receptor for 2-MeO-E2 present in human breast cancer cells, and we will determine its protein and DNA sequences (described under Specific Aim 1). (ii) To determine whether the endogenously-formed or exogenously-administered 2-MeO-E2 (at physiologically-relevant concentrations) has chemoprotective effects against estrogen-induced mammary tumor formation in a commonly-used animal model. We will determine the potency and efficacy of the exogenously-administered 2-MeO-E2 for protection against estradiol-induced mammary tumorigenesis in female ACI rats, and we will also evaluate the mammary cancer-protective effects of the endogenously-formed 2-MeO-E2 by determining whether chronic administration of entacapone (a selective COMT inhibitor) alters estradiol-induced mammary carcinogenesis in the female ACI rats. These studies are described under Specific Aims 2, 3, and 4. Our proposed studies are expected to advance our knowledge on the mammary cancer-protective effects of 2- MeO-E2, a nonpolar endogenous estrogen metabolite formed in large amounts in humans. This knowledge will form the basis for future development of new approaches to the prevention of human mammary cancer by administration of "physiological doses" of 2-MeO-E2 (or its synthetic analogs), or by using agents that can alter the metabolic formation and/or disposition of endogenous 2-MeO-E2 in beneficial ways. The results will also provide novel mechanistic understanding for the biological actions of 2-MeO-E2.