Breast Cancer Therapeutics, Environmental Estrogens, and the Estrogens Receptor (ER); Characterization of the Diverse Ligand Binding Properties of the ER.

摘要

The estrogen receptor (ER) is found in the nucleus of several tissues, including breast, bone, liver, the organs of the reproductive system, and the cardiovascular system. The ER binds several types of compounds, including compounds that are quite distinct from its natural ligand. Estrogens bind to and activate the ER, which leads to the stimulation of transcription of genes containing an estrogen responsive element (ERE). Antiestrogens and partial antiestrogens bind tightly to the ER but fail to activate transcription; these compounds are currently in widespread use for the treatment of breast cancer. In addition, a variety of compounds introduced into the environment by human activity have also been found to act as estrogen mimics and alter reproductive function and development. The goals of this project are to understand, on a molecular level, how the ER binds estrogens, anti-estrogens, and estrogen mimics present in the environment, how this binding triggers activity, and how mutations in the ER discovered in breast cancer patients affect ER activity. Towards this end, we have expressed and purified the ligand binding domain of the estrogen receptor, and studied complexes with estradiol, the natural ligand, and tamoxifen, a partial antiestrogen in use as a breast cancer therapeutic using high-resolution heteronuclear NMR spectroscopy.