INVESTIGATING THE SPATIAL BINDING OF CADMIUM AND NICKEL ON THE ESTROGEN RECEPTOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 乳腺癌是美国女性最常见的癌症之一，通常发展为雌激素受体(ER)阳性。ER阳性乳腺癌的进展高度依赖于雌激素刺激。最近的研究表明，重金属可能通过模仿雌激素的S效应而参与乳腺癌的发生发展。通常被称为金属雌激素的金属，如镉和镍，已被证明激活ER信号通路，并有助于乳腺癌的发生。来自我的实验室和其他人的数据表明，镉和镍的作用是内质网依赖的，多项研究表明镉与雌激素受体结合；然而，结合的位置仍然存在争议，需要进一步分析。为了剖析镉和镍激活ER的机制，我们提出了识别雌激素受体上的金属相互作用区域的具体目的如下：1)利用扩展X射线吸收精细结构(EXAFS)识别参与雌激素受体中镉和镍配位的邻近原子；2)利用显微探针和透射式X射线显微镜(TXM)结合荧光显微镜在体内识别金属-ER复合体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Breast cancer, one most common cancer that occurs in women in the United States, often develops as estrogen receptor (ER) positive. The progression of ER positive breast cancer is highly dependent on estrogenic stimulation. Recent studies have suggested that heavy metals may contribute to the development of breast cancer by mimicking estrogen?s effect. Often referred to as metalloestrogens, metals like cadmium and nickel have been shown to activate the ER signaling pathway and contribute to mammary gland carcinogenesis. Data from my lab and others have suggested that the actions of cadmium and nickel are ER dependent and multiple studies have demonstrated that the cadmium binds to the estrogen receptor; however, the location of binding remains controversial and requires further analysis. In order to dissect the mechanism of ER activation by cadmium and nickel, we propose to identify the metal interaction domain on the estrogen receptor with the following specific aims: 1) Identify the neighboring atoms involved in the coordination of cadmium and nickel in estrogen receptor using EXAFS (Extended X-ray Absorption Fine Structure), and 2) Identify the metal-ER complex in vivo using microprobe and transmission x-ray microscopy (TXM) in conjunction with fluorescent microscopy.