4-Hydroxyestradiol Receptor in Breast Cancer

描述(申请人提供)：越来越多的证据表明，4-羟基雌二醇在动物体内通过雌二醇(E2)诱导癌症，并可能在人类中引发乳腺癌和其他与激素相关的癌症。4-羟基雌二醇的这种病理生理作用是由其在E_2诱发肿瘤的啮齿动物组织或人乳腺和子宫组织中的特异性生物合成以及4-羟基雌二醇对啮齿动物组织的DNA损伤和肿瘤的诱导所支持的。已知的4-羟基雌二醇的生理作用包括诱导子宫胚泡着床和上调子宫乳铁蛋白基因的表达，与雌二醇组的不到两倍相比，载药组是对照组的60倍。这些数据表明，4-羟基雌二醇具有不同于雌二醇的激素作用。我们的假设是，4-羟基雌二醇作为一种激素与其自身的受体结合。这种4-羟基雌二醇受体介导的激素作用可能调节子宫和乳腺中的细胞增殖和其他生物事件。细胞失去对4-羟基雌二醇形成和分解代谢的控制可能会导致病理生理后果，导致肿瘤在子宫、乳房和其他地方发生和生长。为了验证这一假设，我们首先需要分离假定的4-羟基雌二醇受体并对其进行表征。具体来说，我们计划：1.合成4-羟基雌二醇连接的Sepharose6B，并将其用于从小鼠子宫组织中分离受体；2.分离足够纯净的蛋白质，用于部分序列，用于获得部分基因序列。这项计划符合乳腺癌进展审查小组的目标1和3，以更好地了解正常乳腺和癌前病变的生物学。

DESCRIPTION (provided by applicant): There is increasing evidence that 4-hydroxyestradiol mediates the induction of cancer by estradiol (E2) in animals and possibly breast and other hormone-associated cancer in humans. This pathophysiological role of 4-hydroxyestradiol is supported by its specific biosynthesis in tissues of rodents where E2 induces tumors or in human breast and uterine tissue and by the induction of DNA damage and of tumors in rodent tissues by 4-hydroxyestradiol. Known physiological roles of 4-hydroxyestradiol include induction of blastocyst implantation in the uterus and upregulation of uterine lactoferrin gene expression 60 fold over vehicle controls compared to less than a doubling by E2. These data indicate a hormonal role of 4- hydroxyestradiol distinct and different from that of E2. Our hypothesis is that 4-hydroxyestradiol acts as a hormone binding to its own receptor. This 4-hydroxyestradiol receptor-mediated hormone action may regulate cell proliferation and other biological events in the uterus and mammary gland. Loss of cellular control over 4-hydroxyestradiol formation and catabolism may induce pathophysiological consequences resulting in tumor initiation and growth in the uterus, breast and elsewhere. In order to examine this hypothesis, we first need to isolate the putative 4-hydroxyestradiol receptor and characterize it. Specifically, we plan to: 1. Synthesize 4-hydroxyestradiol-linked sepharose 6B and use it to isolate the receptor from mouse uterine tissue, and 2. isolate sufficiently pure protein for a partial sequence, which will be used to obtain a partial gene sequence. This plan is in line with goals 1 and 3 of the Breast Cancer Progress Review Group to better understand the biology of the normal mammary gland and of precancerous lesions.