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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 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，重金属可能有助于乳腺癌的发展，模仿雌激素？s效应。通常被称为金属雌激素，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。来自我实验室和其他实验室的数据表明，镉和镍的作用依赖于雌激素受体，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雌激素受体的机制，我们建议确定雌激素受体上的金属相互作用域，具体目标如下：1）用EXAFS确定雌激素受体中参与镉和镍配位的相邻原子（扩展X射线吸收精细结构），（2）用微探针和透射X射线显微镜（TXM）结合荧光显微镜在体内鉴定金属-ER复合物。

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.