2-METHOXYESTRADIOL & HORMONAL CANCER

描述（由申请人提供）：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二醇代谢物）的代谢物o -甲基化形成。2-MeO-E2在非生理性高浓度下具有抗增殖、凋亡和抗血管生成作用。这项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其特异性细胞受体来研究2-MeO-E2作用的分子机制。我们将在人乳腺癌细胞中分离出一种特异性的、高亲和力的2-MeO-E2细胞受体，并确定其蛋白质和DNA序列（见specific Aim 1）。（ii）在常用的动物模型中，确定内源性形成或外源性给药的2-MeO-E2（生理相关浓度）是否对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2-MeO-E2在雌性ACI大鼠中对雌二醇诱导的乳腺肿瘤发生的保护作用和功效，我们还将通过确定长期给药恩他卡酮（一种选择性COMT抑制剂）是否改变雌二醇诱导的雌性ACI大鼠的乳腺癌发生来评估内源性2-MeO-E2的乳腺癌保护作用。具体目标2、3和4中描述了这些研究。我们提出的研究有望提高我们对2- MeO-E2的乳腺癌保护作用的认识，2- MeO-E2是一种在人体中大量形成的非极性内源性雌激素代谢物。这些知识将为未来开发新的预防人类乳腺癌的方法奠定基础，通过给药“生理剂量”的2-MeO-E2（或其合成类似物），或通过使用能够以有益的方式改变内源性2-MeO-E2代谢形成和/或处置的药物。该结果也将为2-MeO-E2的生物学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.