Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer.
Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer.
复制标题
DOI：
10.1038/s41388-022-02527-z
复制
发表时间：
2022-12
期刊：
影响因子：
8
通讯作者：
Keyomarsi, Khandan
中科院分区：
文献类型：
--
作者：
Li, Mi;Tsavachidis, Spiridon;Wang, Fuchenchu;Bui, Tuyen;Tuyen Duong Thanh Nguyen;Luo, Linjie;Multani, Asha S.;Bondy, Melissa L.;Hunt, Kelly K.;Keyomarsi, Khandan
低分子量周期蛋白E （LMW-E）是一种n端缺失（40个氨基酸）形式的周期蛋白E，在乳腺癌中检测到，但在正常细胞或组织中没有发现。LMW-E过表达与肿瘤增殖率无关，可预测乳腺癌患者的生存率较差，但LMW-E的致癌机制及其独立于全长周期蛋白E （FL-cycE）的独特功能尚不清楚。在目前的研究中，我们发现LMW-E与早期乳腺肿瘤（n = 725）的基因组不稳定性相关，并促进人类乳腺上皮细胞（hMECs）的基因组不稳定性。从机制上讲，FL-cycE过表达通过复制应激和DNA损伤积累抑制hMECs的增殖，而LMW-E通过上调DNA复制和损伤修复促进复制应激耐受。具体来说，LMW-E与染色质相互作用，以CDC6依赖的方式上调微染色体维持复合体蛋白（mcm）的负载，并以RAD51和c17orf53依赖的方式促进DNA修复。ATR抑制剂（ceralasertib）、CHK1抑制剂（rabusertib）或RAD51抑制剂（B02）靶向ATR-CHK1-RAD51通路，可显著降低过表达lw - e的hMECs和乳腺癌细胞的活力。总的来说，我们的研究结果描述了LMW-E在由复制应激耐受性和基因组不稳定性介导的肿瘤发生中的新作用，为LMW-E过表达的乳腺癌提供了新的治疗策略。
Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promotes genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibits the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitates replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E–overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E–overexpressing breast cancers.
登录
查看更多内容
影响因子：
11.5
作者：
Kettner, Nicole M.;Vijayaraghavan, Smruthi;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
11.2
作者：
Akli, Said;Van Pelt, Carolyn S.;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
11.2
作者：
Caruso, Joseph A.;Hunt, Kelly K.;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
10.5
作者：
Ge, Xin Quan;Jackson, Dean A;Blow, J Julian
通讯作者：
Blow, J Julian
影响因子：
5.5
作者：
Fagundes R;Teixeira LK
通讯作者：
Teixeira LK