This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.