ESTROGEN RECEPTOR VARIANTS AND BREAST CANCER

描述：该提案提出了一个假设， 雌激素受体（ER）中发生的突变影响ER二聚化， 与其他细胞蛋白质的相互作用和转录活性。 使用酵母双杂交系统，申请人先前已经表明， 雌激素诱导wtER蛋白的二聚化， 抗雌激素，他莫昔芬和ICI 182，780，破坏雌激素诱导的 wtER的二聚化。 这项建议将把这些研究扩展到ER， 变异，和两个雌激素受体相关蛋白，通过四个特定的 目的利用酵母双杂交系统。 在第一个目标中， 雌激素诱导变异型/突变型ER二聚化以及 抗雌激素对这一过程的影响将被探讨。 目标2将确定， 缺失或点ER突变体影响wtER的转录活性 在雌激素和抗雌激素存在和不存在的情况下。 在aim 3中， 两种雌激素受体相关蛋白ERAP 140和 RIP 140与wtER以及在存在和不存在配体的情况下彼此 将被研究。 在目标4中，几个ER之间的相互作用 将检查变体/突变体和ERAP 140或RIP 140。 这些研究 应该有助于解决导致发展的分子机制， 乳腺癌中激素抵抗的进展。

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.