水通道蛋白1（AQP1）在乳腺癌浸润转移及紫杉醇敏感性中的作用及分子机制研究

The invasion/metastasis and chemotherapy resistance are the main causes of death in breast cancer patients, so it is important to investigate the molecular mechanisms. Our study has indicated that water channel protein 1 (AQP1) has higher expression in breast cancer comparing to normal breast tissues, and especially AQP1 expression is concentrated in the infiltrating edge of tumor tissues instead of the core of cancer. In the mammary gland of normal and benign lesions, AQP1 expression is in ductal myoepithelial and the glandular cells almost have no AQP1 expression, but there is significant expression of AQP1 in breast cancer cells. In addition, AQP1 is localised on the membrane of normal breast ductal, while its expression is re-localised in the cytoplasm of breast cancer cells. Over expression of AQP1 in the MDA-MB-231 breast cancer cells resulted in the lower sensitivity to paclitaxel than the control cells. Therefore, according to our previous study and the literature, we indicate that the expression of AQP1 has critical role in the invasion/ metastasis and paclitaxel resistance of breast cancer. In this project, we will further investigate the molecular mechanisms of AQP1 in invasion/metastasis and paclitaxel resistance of breast cancer by using breast cancer cell lines, primary breast cancer cells and the clinical materials.

乳腺癌浸润转移及化疗耐药是导致患者死亡的主要原因，探索其分子机制有重要临床意义。课题组前期研究发现水通道蛋白1（AQP1）在乳腺癌组织中表达显著增高，且浸润边缘肿瘤细胞表达高于中心部分；在乳腺正常及良性病变中，AQP1表达于导管肌上皮，腺上皮几乎无着色，而乳腺癌细胞中出现明显的AQP1表达；另外，与正常乳腺导管AQP1胞膜定位相比，乳腺癌细胞呈现AQP1胞浆再定位；且降表达AQP1的MDA-MB-231细胞对紫杉醇敏感性显著降低。综合分析课题组前期结果和文献，AQP1与乳腺癌浸润转移及紫杉醇药物敏感性密切相关。本研究将在前期工作基础上，利用乳腺癌细胞株、原代培养乳腺癌细胞和乳腺癌临床标本等材料，通过各种分子/细胞生物学方法等实验手段，结合患者临床资料，从体外到体内，从基础研究到临床资料分析，深入研究AQP1在乳腺癌浸润转移及紫杉醇耐药方面的分子机制，为临床乳腺癌个体化治疗提供新靶点和思路。

水通道蛋白1（AQP1）是一种跨膜疏水性蛋白，属于高度保守的水通道蛋白家族。虽然越来越多的证据表明AQP1的胞浆定位很重要，但是较少有人研究其胞浆分布的功能。在我们的临床研究中，我们首次发现AQP1在浸润性导管癌乳腺癌患者中主要呈胞浆分布，且其胞浆表达是一个独立的预后因素。AQP1蛋白高表达提示较短的生存期，特别是在Luminal亚型中。此外，与我们在临床上的的研究结果一致，我们在原代培养的细胞以及过表达AQP1的乳腺癌细胞中进一步验证了这一结果。并且，研究中我们还惊喜地发现AQP1胞浆高表达患者可从CEF方案中获益,不能从CMF方案中获益,提示AQP1胞浆表达与蒽环类药物疗效密切相关。总之，我们的研究表明AQP1胞浆表达会促进乳腺癌进展，并且首次为其胞浆表达可能是乳腺癌的一个潜在的预后标志物提供了证据。下一步我们将继续探究AQP1胞浆表达可作为乳腺癌蒽环类药物疗效的标志物以及深入研究蒽环类药物敏感性方面的分子机制。