UCH-L1调控雌激素受体的分子机制及对雌激素拮抗剂乳腺癌治疗的影响

雌激素受体（Estrogen receptor，ER）的状态是预测乳腺癌对内分泌治疗效果和预后的关键指标之一，但大约有三分之一的乳腺癌是呈ER阴性的。ER阴性乳腺癌细胞分化程度低，易转移且治疗及预后效果差。因此，阐明调控ER表达的分子机制可能为乳腺癌治疗提供新的策略和方法。申请人前期研究发现，乳腺癌细胞中泛素羧基末端水解酶UCH-L1与ERα表达呈负相关。ERα阴性和阳性细胞中UCH-L1蛋白分别显示出高表达和低表达，在ERα阳性细胞中过表达UCH-L1则导致ERα水平明显下调。本课题拟深入研究UCH-L1调控ERα表达的分子机制，阐明UCH-L1对ERα泛素化及蛋白降解的影响，探索UCH-L1对组蛋白泛素化及对ERα基因表达的调控作用；确定靶向UCH-L1对雌激素拮抗剂乳腺癌治疗效果的影响。本项目研究旨在揭示新的调控ERα表达的分子机制，为提高乳腺癌（包括ER阴性）的治愈率提供科学依据。

The status of estrogen receptor (ER) in breast cancer is usually associated with prognosis and response to hormonal therapy. ER status varies among breast cancers, with one-third of the disease showing ER-negative. Absence of ER is known to be associated with poor differentiation of tumor cells, resistance to hormonal therapy, and poor clinical outcome; thus, a better understanding of the causes and mechanisms underlying the loss or reduction of ER in breast cancer may help identify novel strategy for treating breast cancer. We recently found that the expression of ubiquitin C-terminal hydrolase-L1 (UCH-L1), an enzyme that uniquely possesses both ubiquitin hydrolase and ligase activity, is conversely related with ERα status in breast cancer. UCH-L1 is overexpressed in ER(-) cell lines, but is barely detectable in ER(+) cell lines. Transfection of ER(+) cells with an UCH-L1 expression vector resulted in a remarkable reduction of ERα content. These results implicate a role of UCH-L1 in the down-regulation of ERα in breast cancer. This proposal is aimed at exploring the role of UCH-L1 in regulating ERα degradation and gene expression in human breast cancer cells and the therapeutic implication. We will test the hypothesis that overexpression of UCH-L1 contributes to the development of hormone-independent breast cancer by facilitating the degradation of ERα or/and by repressing the gene expression of the receptor, and that targeting this enzyme can sensitize hormone-resistant human breast cancers to the selective estrogen receptor modulators such as tamoxifen, the most commonly used anti-estrogen agent in the treatment of this disease. The proposed study may not only provide a basis for new approaches to up-regulating or maintaining ER level, but also present a new rationale for developing more effective and better therapies for breast cancer, and a new pharmacologic target for drug development.