ESTROGEN RECEPTOR VARIANTS AND BREAST CANCER

描述：这项提议解决了这样一个假设，即 雌激素受体(ER)发生突变会影响ER二聚化， 与其他细胞蛋白的相互作用，以及转录活性。 使用酵母双杂交系统，申请人先前已经证明 雌激素诱导WTER蛋白二聚化 抗雌激素他莫昔芬和ICI182,780阻断雌激素诱导 水的二聚化。这项建议将把这些研究扩展到ER、ITS 变异体和两个雌激素受体相关蛋白通过四个特定的 目的采用酵母双杂交系统。在第一个目标中， 雌激素诱导突变型/突变型内质网二聚化及其作用 将探索抗雌激素在这一过程中的作用。目标2将确定 ER缺失或点突变会影响WTER的转录活性 在存在和不存在雌激素和抗雌激素的情况下。在目标3中， 雌激素受体相关蛋白ERAP140和ERAP140的相互作用 RIP140与WTER以及在存在和不存在配体的情况下相互作用 将会被研究。在目标4中，几个ER之间的相互作用 将检查变异体/突变体和ERAP140或RIP140。这些研究 应该有助于解决导致发育和 乳腺癌激素抵抗的研究进展。

DESCRIPTION: This proposal addresses the hypothesis that naturally occurring mutations in estrogen receptor (ER) affect ER dimerization, interaction with other cellular proteins, and transcriptional activity. Using the yeast two hybrid system, the applicant has previously shown that estrogen induces dimerization of the wtER protein and that the antiestrogens, tamoxifen and ICI 182,780, disrupt estrogen-induced dimerization of wtER. This proposal will extend these studies to ER, its variants, and two estrogen receptor associated proteins via four specific aims using the yeast two hybrid system. In the first aim the ability of estrogen to induce dimerization of variant/mutant ER as well as the effects of antiestrogens on this process will be explored. Aim 2 will ascertain if deletion or point ER mutants affect the transcriptional activity of the wtER in the presence and absence of estrogen and antiestrogens. In aim 3 the interaction of two estrogen receptor associated proteins, ERAP140 and RIP140, with wtER and with each other in the presence and absence of ligand will be studied. In aim 4 the interactions between several ER variants/mutants and ERAP140 or RIP140 will be examined. These studies should help to address the molecular mechanisms leading to development and progression of hormone resistance in breast cancer.