DNA修复蛋白PARP-1对BRCA基因突变乳腺癌放射敏感性的影响及调控机制

Parts of locally advanced breast cancers (LABC) are with BRCA mutations, most of which are triple negative breast cancers. Their operation effect is poor and they have no chance for endocrine or targeted therapy. Therefore, how to enhance their radiosensitivity is the pressing problem to be solved. The ability of DNA repair directly influences the radiosensitivity of tumor cells, and PARP-1 and BRCA are the key repair protein for DNA single-strand and double-strand respectively, especially the BRCA is closely related to the development of breast cancer. This project uses the cell lines and primary cells of BRCA-mutated breast cancers to explore the impact of PARP-1 inhibitors on the radiosensitivity ofthese breast cancers and establish the PARP-1-PI-3K/Akt-BRCA signaling pathway in the process of irradiation. Finally, the establishment of NOD/SCID mouse xenograft model of breast cancer primary cells with BRCA mutations is applied to confirm the regulationary mechanism of PARP-1-PI-3K/Akt-BRCA signaling pathway in vivo. Briefly, the project is the first time to use the primary cells of BRCA-mutated breast cancers to study jointly the impact of the two most important repair proteins PARP-1 and BRCA on the radiosensitivity of breast cancer and the regulationary mechanism of PARP-1-PI-3K/Akt- BRCA signaling pathway in the irradiation process in order to open up new ideas to enhance the radiosensitivity of LABC with BRCA mutations.

局部晚期乳腺癌中一部分是BRCA突变乳腺癌（多是三阴乳腺癌），手术效果差，又无内分泌或靶向治疗机会，如何提高其放射敏感性是丞待解决的难题。DNA修复能力直接影响细胞的放射敏感性，PARP-1和BRCA分别是DNA单链和双链修复的关键蛋白，而BRCA与乳腺癌发生、发展关系密切。本课题以BRCA突变乳腺癌细胞株和原代细胞为研究对象，探讨PARP-1抑制剂对其放射敏感性的影响，并在照射过程中建立PARP-1-PI-3K/Akt-BRCA信号通路，最后建立BRCA突变乳腺癌原代细胞的NOD/SCID鼠移植瘤模型，在体验证此信号通路的调控机制。本课题首次以BRCA突变乳腺癌原代细胞为对象，联合研究两个最重要的修复蛋白PARP-1和BRCA对乳腺癌放射敏感性的影响，特别探讨PARP-1-PI-3K/Akt-BRCA信号通路在照射过程中的调控机制，为提高局部晚期BRCA突变乳腺癌的放射敏感性开创新思路。

放射治疗是恶性肿瘤最重要的治疗手段之一，如何提高肿瘤的放疗敏感性是目前放射生物研究中最热门的方向。DNA 修复能力直接影响细胞放射敏感性，PARP-1 和BRCA 分别是DNA 单链和双链修复关键蛋白，晚期乳腺癌中一部分是BRCA 突变乳腺癌（多是三阴乳腺癌），手术效果差，又无内分泌或靶向治疗机会，而BRCA 与乳腺癌发生发展关系密切。鼻咽癌和肺癌放射抗拒的产生也是鼻咽癌放疗后未控和复发的最重要原因。本课题以BRCA 突变乳腺癌细胞株和鼻咽癌为研究对象，探讨PARP-1抑制剂对其放射敏感性的影响，并在照射过程中建立PARP-1—PI-3K/Akt—BRCA 信号通路，并明确自噬在放射线引起DNA损伤介导的细胞凋亡中的促存活功能以及PARP-1在此过程中的作用，确立信号通路LKB1-AMPK-mTOR在此过程中的调控机理。并建立了肺癌放射抗拒细胞株，并探讨了VEGF和Notch1在肺癌放射抗拒形成过程中的作用机制。为提高局部晚期BRCA 突变乳腺癌和鼻咽癌及肺癌的放射敏感性开创新思路。