Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance./nMethods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms./nResults: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization./nConclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.

中文翻译：

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SYTL4下调三阴性乳腺癌中的微管稳定性并赋予紫杉醇耐药性

背景：紫杉烷类药物是三阴性乳腺癌（TNBC）患者的一线化疗药物。但是，化学抗性会降低其有效性。我们假设新辅助化疗（NAC）之前和之后的肿瘤样品的分子谱分析将有助于鉴定与耐药性相关的基因。/n方法：我们通过RNA测序对8例TNBC的NAC患者中的10个样品进行了测序：3例病理完全响应（pCR），其他5个为非pCR。通过小规模的siRNA库，选择能够预测化学疗法应答的差异表达基因进行体外功能筛选。TNBC中感兴趣的基因的临床和功能意义在体外和在体内，和生物化学测定和成像分析被应用到研究mechanisms./n结果：突触结合蛋白样4（SYTL4），小泡转运一个拉布效应，被确定为领先的功能候选。SYTL4高表达表明在多个TNBC队列中预后较差，特别是在紫杉烷处理的TNBC中。SYTL4被鉴定为一种新的化学抗性基因，已在TNBC细胞，小鼠模型和患者来源的类器官中得到验证。从机制上讲，SYTL4的下调稳定了微管网络并减慢了微管的生长速度。此外，SYTL4与微管共定位，并通过其包含接头和C2A域的中间区域与微管相互作用。最后，我们发现SYTL4能够结合微管并抑制在体外微管polymerization./n结论： SYTL4是在TNBC一种新颖的化学抗性基因和它的上调表明紫杉烷治疗TNBC预后不良。此外，SYTL4直接结合微管并降低微管稳定性。