TEKT4 中的富集变异与紫杉醇治疗乳腺癌的耐药性相关。

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel.

机构信息

1] Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China [2].

Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

出版信息

Nat Commun. 2014 May 13;5:3802. doi: 10.1038/ncomms4802.

DOI:10.1038/ncomms4802

PMID:24823476

Abstract

Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

摘要

在化疗药物中，紫杉醇对乳腺癌显示出巨大的疗效。紫杉醇反应的预测可能会改善患者的预后。在这里，我们通过外显子组测序显示，与治疗前活检相比，两种 TEKT4 种系变异在治疗后肿瘤中富集。我们在 84 对样本的独立队列中发现了约 10%的 Tektin4 变异。Tektin4（由 TEKT4 编码）与二联体微管中的微管蛋白密切相关，并有助于稳定这些结构。这两种高顺式连锁的 TEKT4 种系变异具有生物学相关性，因为变异 TEKT4 的异位表达会使微管稳定性失调，拮抗紫杉醇诱导的微管稳定作用，并增加紫杉醇耐药性。此外，与野生型 TEKT4 相比，携带 TEKT4 种系变异的患者在接受紫杉醇为基础的化疗后，无病生存率和总生存率降低。综上所述，我们揭示了乳腺癌通过获得种系变异对紫杉醇产生耐药性的潜在机制。