Breast Cancer Risk-Associated SNPs in the mTOR Promoter Form De Novo KLF5-and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel
Breast Cancer Risk-Associated SNPs in the mTOR Promoter Form De Novo KLF5-and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel
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mTOR 启动子中与乳腺癌风险相关的 SNP 从头形成 KLF5 和 ZEB1 结合位点，影响细胞对紫杉醇的反应
DOI：
10.1158/1541-7786.mcr-18-1072
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发表时间：
2019-11-01
影响因子：
5.2
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
Chen, Qiuchen;Deng, Xiaolan;Wei, Minjie
ZEB 1（一种正性增强子）和KLF 5（一种负性沉默子）影响转录因子，并在肿瘤发生和多药耐药中发挥固有的保守作用。在人类中，mTOR启动子位点的rs 2295080 T等位基因与人类癌症风险相关;然而，另一个SNP rs 2295079的63 bp间隔尚未确定。在这里，我们首次发现rs 2295079（-78C/G）和rs 2295080（-141G/T）形成连锁单倍型，Ht 1（-78C/-141G）和Ht 2（-78G/-141T）占主导地位，这与乳腺癌的不同易感性，紫杉醇的反应和乳腺癌的临床结局相关。在细胞水平上，与Ht 1相比，Ht 2在促进mTOR表达方面表现出更强的作用，导致肿瘤细胞生长增强和对PTX治疗的抗性增强。从机制上讲，Ht 2的-141 T等位基因创造了一个新的ZEB 1结合位点;同时，Ht 1的-78 C等位基因作为一个新的KLF 5结合位点存在，通过ZEB 1/KLF 5-mTOR-CCND 1/ABCB 1级联协同诱导促进/抑制mTOR表达、细胞增殖和细胞毒性药物的分泌，从而影响体内和体外对紫杉醇治疗的反应。我们的研究结果表明，人类细胞中存在ZEB 1/KLF 5-mTOR-CCND 1/ABCB 1轴，可能参与紫杉醇反应途径，并在功能上调节个体化乳腺癌易感性和预后。
ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5-mTOR-CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5-mTOR-CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.