核IKKα-FAT10信号通路诱发激素依赖型乳腺癌抵抗他莫昔芬治疗机制的研究

Endocrine therapy that blocks estrogen signals is currently the most effective treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, efficacy is often compromised by the development of resistance. The mechanisms that confer breast cancer endocrine-resistance are largely unknown. Our preliminary studies have demonstrated that the expression of nuclear IKKα and FAT10 significantly correlates with relapse and metastasis in tamoxifen (TAM)-treated ER-positive human breast cancer. Further, our studies have shown that activated nuclear IKKα induces FAT10 expression, and that both nuclear IKKα and FAT10 are necessary for TAM-resistance of ER+ MCF7 and T47D cells in vitro. Thus, we hypothesize that the IKKα-to-FAT10 pathway contributes to breast cancer TAM-resistance. Accordingly, we will establish stable breast cancer cell lines expressing constitutively activated IKKα(IKKαEE) or nuclear localization defective IKKαEE (IKKαEE-ΔNLS) to investigate the role of nuclear IKKα in the formation of TAM-resistant breast cancer. We will establish stable breast cancer cell lines with high expression or knockdown of FAT10 to investigate the role of FAT10 in the formation of TAM-resistant breast cancer. We will employ genetic, molecular biology and biochemical techniques to define the mechanisms by which IKKα induces FAT10 expression. We believe that these studies will lay the foundation for identifying new clinical biomarkers for the prediction of TAM-resistance and for developing novel therapeutic strategies for the treatment of TAM-resistant breast cancer.

乳腺癌内分泌治疗耐药是制约其疗效的瓶颈，其发生机理尚不完全清楚。我们前期研究发现，肿瘤细胞中FAT10和核内IKKα的高丰表达与雌激素受体阳性乳腺癌他莫昔芬(TAM)治疗后复发和转移呈显著正相关，而且核内IKKα的激活上调FAT10的表达。据此，我们提出：核IKKα-FAT10信号通路的激活是导致雌激素受体阳性乳腺癌抵抗TAM治疗的重要机制。为此，项目拟通过建立稳定表达核IKKα和核IKKα表达缺失的乳腺癌细胞系、FAT10稳定高表达和FAT10稳定敲低的乳腺癌细胞系，在细胞水平和裸鼠移植瘤模型上分析核IKKα和FAT10在乳腺癌抵抗TAM治疗中的作用。采用基因干扰、染色质免疫共沉淀、荧光素酶报道、移植瘤模型等技术阐明乳腺癌细胞中核IKKα调节FAT10表达的分子机理。项目研究结果将揭示乳腺癌抵抗TAM治疗的新机制，为乳腺癌内分泌治疗增敏、靶向治疗以及内分泌治疗敏感性的预测提供靶标。

乳腺癌内分泌治疗耐药是制约其疗效的瓶颈，其发生机理尚不完全清楚。本课题研究最初发现，临床乳腺癌细胞中FAT10和核内IKKα的高丰表达与雌激素受体阳性乳腺癌他莫昔芬(TAM)治疗后复发和转移呈显著正相关，而且核内IKKα的激活上调 FAT10的表达。项目进一步通过建立稳定表达核IKKα和核IKKα表达缺失的乳腺癌细胞系、FAT10稳定高表达和FAT10稳定敲低的乳腺癌细胞系，在细胞水平和裸鼠移植瘤模型上分析发现核IKKα和FAT10在乳腺癌抵抗TAM治疗中发挥着重要作用。采用基因干扰、染色质免疫共沉淀、荧光素酶报道、移植瘤模型等技术阐明乳腺癌细胞中核IKKα通过与转录因子Pax5作用而调节FAT10的表达。核IKKα-Pax5-FAT10通路的活化引发乳腺癌抵抗TAM的治疗。另外，本课题还发现，IKKα-p53-miR-23a通路可协调IKKα对FAT10表达的调节作用，其中IKKα的激活能减弱p53对FAT10表达的抑制作用。于是，本研究揭示乳腺癌抵抗TAM治疗的新机制，确立了IKKα-to-FAT10信号途径作为治疗Tam耐药ER +乳腺癌的新治疗靶点，对提高乳腺癌病人的治疗效果和质量具有重要的意义。