Skp2调节PPARγ亚细胞定位对乳腺癌预后的影响及机制研究

Nuclear hormone receptor family member PPARγ plays an important role in mammary gland tumorigenesis. Nucleic localization of PPARγ is commonly associated with better prognosis in many malignancies. Skp2 is oncogenic, and its frequent amplification and overexpression correlate with the grade of malignancy in certain tumors. This study aims to examine and correlate the subcellular localization of PPARγ and Skp2 expression with poor prognosis in breast cancer, and investigate the mechanisms that Skp2 regulate cytoplasmic localization of PPARγ. First，subcellular localization of PPARγ and Skp2 expression will be analyzed in 200 paraffin-embedded human breast carcinomas sections by immunohistochemistry. Then correlations will be analyzed between IHC-assessed level of these molecules and major clinicopathological variables and follow-up data. Furthermore, we study that Skp2 overexpression have the effect on subcellular localization of PPARγ in breast cancer cell in vitro. In the end, we will clarify the effectiveness and possible mechanism that cytoplasmic localization of PPARγ can serve as a valuable prognostic marker for breast cancer. This study will provide new targets and new ideas for the estrogen receptor-negative breast cancer prevention and treatment.

核激素受体超家族成员PPARγ在乳腺癌的发生发展中起重要作用， 其核定位通常是许多恶性肿瘤预后良好的指标之一。癌基因Skp2的扩增和过表达通常与肿瘤的恶性程度相关。本课题主要探讨PPARγ胞浆定位和Skp2表达与乳腺癌不良预后的相关性，并分析Skp2对PPARγ亚细胞定位的调节机制。该课题采用免疫组化方法分析200例乳腺癌石蜡包埋标本中PPARγ的亚细胞定位和Skp2表达情况以及它们与乳腺癌患者临床病理特征和预后的关系；在体外研究过表达Skp2基因对PPARγ亚细胞定位的影响及作用机制，并阐明胞浆定位的PPARγ作为乳腺癌不良预后有价值标记物的有效性和可能机制。该研究将为雌激素受体阴性乳腺癌的预防和治疗提供新靶点和新思路。

核激素受体超家族成员PPARγ在乳腺肿瘤中发挥重要作用。先前的研究显示PPARγ经十四烷酰佛波醇乙酸酯处理能发生核浆转位。然而，在乳腺肿瘤中PPARγ在胞浆中的功能尚不清楚。Skp2是一种癌基因，它在某些肿瘤中的扩增和过表达通常与肿瘤的恶性程度相关。本文主要研究PPARγ的胞浆定位和Skp2表达在乳腺癌进程中的作用。首先，对70例乳腺癌和良性乳腺疾病患者石蜡包埋标本免疫组化分析PPARγ的胞浆表达和Skp2表达情况；其次，免疫印迹和免疫荧光技术在乳腺癌细胞中进一步研究二者的相互关系，结果显示乳腺癌中PPARγ的胞浆表达与Skp2表达呈正相关（p<0.05）,与雌激素受体表达和组织学分级有相关性，p值分别为0.06和0.029。此外，在乳腺癌细胞中过表达Skp2能引起PPARγ以MEK1依赖的机制发生核浆转位，使用RNA干扰技术下调Skp2的表达能明显抑制TPA诱导PPARγ核定位。综上所述，PPARγ的亚细胞定位将可能成为治疗乳腺癌新的靶点。