ERLIN2促进乳腺癌细胞生长及调控Herceptin耐药性的分子机制研究

Our Previous analysis from the breast cancer cell line and speciman has led us to identify an endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of candidate oncogenes in approximately 15% human breast cancer , particularly in luminal subtype, and is associated with poor prognosis. In our preliminary study, we found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein are present in both luminal and Her2 subtypes of breast cancer. The gain- and loss-of-function approaches demonstrated that ERLIN2 is a pro-growth factor for the breast cancer cells. The cells grow more quickly with knock-in ERLIN2 and slower with knock-out ERLIN2, and MCF10A cells could be transformed by overexpressing ERLIN2 in virto. And we found that ERLIN2 has a relationship to the Herceptin resistance amd other anticancer agents. So we propose this project to investigate deeply the role of ERLIN2 in breast cancer. Firstly, we will investigate deeply the pro-growth function of ERLIN2 in breast cancer in vivo, in vitro and on the specimen from patients. Secondly, we will investigate the regulating effect of ERLIN2 in the herceptin resistance in some breast cancer subtype in vitor and in vivo . Finally, we will look into throughly the molecular mechanism of ERLIN2 in the herceptin resistance and try to find out the full picture of the upstream and down stream pathway in the resistance to Herceptin treatment. The project will shed new light on understanding the mechanism of breast cancer malignancy and might offer a new promising biomarker and therapy target for breast cancer in the

我们前期研究发现一个新的可能乳腺癌癌基因：ERLIN2。该蛋白是一个内质网跨膜蛋白，在约15%乳腺癌中高表达，同时部分Her2受体阳性，与乳腺癌较差预后有明显相关性。体外实验发现该基因具有促进乳腺癌细胞生长、恶性转化乳腺正常上皮细胞的作用，分子机制是抑制内质网应激引起的UPR信号通路所致的细胞凋亡，进一步研究发现ERLIN2与Herceptin及化疗药耐药性具有一定相关性，因此本课题将进一步从细胞、动物以及患者样本水平深入研究其癌基因特征及耐药调控机制，主要内容如下：1.进一步研究ERLIN2调控乳腺癌细胞及荷瘤裸鼠的生长作用。2. ERLIN2对Her2阳性乳腺癌细胞Herceptin耐药的调控作用。3.ERLIN2调控Herceptin耐药性的分子机制研究。希望通过本课题研究，找到新的乳腺癌生物标志物及个体化治疗新靶点，为将来应用于临床提供理论基础与实验依据。

不同亚型的乳腺癌对放化疗具有特异性，其基本机制尚且未知。脂代谢上调是癌产生的主要标志，SREBP-1是脂代谢的关键转录调控因子，也是致癌信号分子，而p53亦是乳腺癌中SREBPs的调控子。项目申请人前期的研究发现OLA1调控氧化应激，OLA1-/-小鼠体脂肪和肝脏组织中脂积累、SREBP1表达水平显著降低。因此，我们推测在不同乳腺癌亚型中观察到的脂质多聚不饱和程度差异是由脂代谢基因的不同表达造成的。本项目中，我们将招募不同亚型、且对放化疗敏感性不同的乳腺癌患者研究OLA1和SREBP1表达水平与乳腺癌亚型和放化疗抗性之间的关联；体外实验，研究通过p53/OLA1/SREBP1相互作用影响放化疗抗性的分子机制；利用动物模型，探讨SREBP1和其下游分子的抗肿瘤效果。我們的研究结果l加深对OLA1/SREBP1相互作用在调控乳腺癌化疗放疗敏感性中作用的理解，为乳腺癌提供一个新的治疗靶点，具有明显的临床应用前景。