FATS调控乳腺癌放疗敏感性的机制研究

we found a new evolutionary conserved fragile sites gene, which was named fragile-site associated tumor suppressor (FATS), and firstly was cloned FATS internationally. Previous studies found that FATS located FRA10F, closely associated with human tumors. Our preliminary data showed that FATS was significantly downregulated in breast cancer and its expression positively correlated with radiosensitivity of breast cancer cells. Radiotherapy significantly increased DFS of breast cancer patients with positive FATS status in.comparison to that of FATS-negative patients. Multivariate cox regression analysis revealed that FATS status was a more valuable predictor of DFS for breast cancer patients receiving radiotherapy. Further study revealed that FATS activated p53 signaling, and subsequently resulted in enhancement of radiation- induced apoptosis. However, much more exact molecular mechanisms about how FATS activated.p53 signaling and radiosensitized breast cancer remain to be further investigated. Therefore, based on these findings, this project will deeply investigate the mechanisms of FATS in inhibiting p53 signaling and sensitizing breast cancer to radiation by employing molecular biology, cell biology techniques, nude mice xenograftic model and clinical sample. Futhermore we will investigate the potential of FATS as a marker for patients radiosensitivity predicting. This project will offer the theocratic basis and experimental evidence for the application of FATS-related targeted therapy into the radiation therapy of breast cancer. All in all, this research would provide us new target and therapeutic strategy for improving the radiotherapy outcome of breast cancer, which is of great clinical significance.

本课题组在前期研究中克隆并命名新的脆性位点基因FATS，并发现与人类肿瘤密切相关。在乳腺癌中我们发现FATS显著下调，过表达FATS增加乳腺癌细胞放疗敏感性。对临床病例研究发现：FATS高表达有更好的预后，FATS是独立预后因素，为研究放疗敏感性奠定了基础。进一步研究发现，FATS可激活p53信号通路，进而促进放疗诱导的细胞凋亡，增加放疗敏感性。但乳腺癌中FATS如何调控p53信号通路进而影响放疗敏感性尚不明确。本项目将在前期基础上，从分子、细胞、模型小鼠及临床患者四个方面深入研究FATS如何调控p53信号通路进而影响放疗敏感性的分子机制，并探讨FATS作为预测乳腺癌放疗敏感性分子靶标的可能性，从而明确FATS放疗增敏作用并阐明其可能的分子机制，本课题的开展将为开发与FATS相关靶向治疗应用于乳腺癌放疗增敏提供理论基础及实验依据，为乳腺癌放射治疗增加新的内容，提供新的思路，具有重要意义。

放射治疗作为目前乳腺癌综合治疗的重要组成部分是控制乳腺癌非常有效的治疗方案，但是患者放疗疗效存在个体差异，究其原因可能由于其放疗敏感性差异所导致，本研究课题基于我们的预实验结果及前期已发表研究的基础上，以过表达和敲低 FATS 的乳腺癌细胞为模型，采用多种体外、体内实验方法，揭示了 FATS 可以增强乳腺癌细胞的放疗敏感性，促进放射治疗对肿瘤的杀伤作用；FATS 调控乳腺癌放疗敏感性的分子机制是p53依赖性的，因此 FATS 可以作为预测患者放疗敏感性的分子标志及指导个性化的个体放疗方案的实施。本课将丰富放疗敏感性分子靶标研究内容，FATS 将是一个全新的与乳腺癌放疗敏感性相关的重要诊断标志物和治疗靶点，这将为临床乳腺癌诊断、预后判断及个体化放射治疗提供理论及实验依据，具有重要理论意义与临床应用价值。