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首页> 外文期刊>Breast cancer research and treatment. >Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers
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Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers

机译：植入相关基因在三重阴性乳腺癌的患者衍生的异种移植模型中的预后和功能重要性

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摘要

We aimed to identify the factors affecting the successful tumor engraftment in breast cancer patient-derived xenograft (PDX) models. Further, we investigated the prognostic significance and the functional importance of the PDX engraftment-related genes in triple-negative breast cancers (TNBC). The clinico-pathologic features of 81 breast cancer patients whose tissues were used for PDX transplantation were analyzed to identify the factors affecting the PDX engraftment. A gene signature associated with the PDX engraftment was discovered and its clinical importance was tested in a publicly available dataset and in vitro assays. Nineteen out of 81 (23.4 %) transplanted tumors were successfully engrafted into the PDX models. The engraftment rate was highest in TNBC when compared to other subtypes (p = 0.001) and in recurrent or chemotherapy-resistant tumors compared to newly diagnosed primary tumors (p = 0.024). PDX tumors originated from the TNBC cases showed more rapid tumor growth in mice. Gene expression profiling showed that down-regulation of genes involved in the tumor-immune interaction was significantly associated with the successful PDX engraftment. The engraftment gene signature was associated with worse survival outcome when tested in publicly available mRNA datasets of TNBC cases. Among the engraftment-related genes, PHLDA2, TKT, and P4HA2 showed high expression in triple-negative breast cancer cell lines, and siRNA-based gene silencing resulted in reduced cell invasion and proliferation in vitro. Our results show that the PDX engraftment may reflect the aggressive phenotype in breast cancer. Genes associated with the PDX engraftment may provide a novel prognostic biomarker and therapeutic targets in TNBC.
机译：我们旨在确定影响乳腺癌患者衍生的异种移植（PDX）模型中成功肿瘤植入的因素。此外，我们研究了三阴性乳腺癌（TNBC）中PDX植入相关基因的预后意义和功能性重要性。分析了81例乳腺癌患者的临床病理特征，其组织用于PDX移植，以确定影响PDX植入的因素。发现了与PDX植入相关的基因签名，并在公共可用的数据集和体外测定中测试其临床重要性。在81中（23.4％）中，移植的肿瘤成功地将其移植到PDX型号中。与新诊断的原发性肿瘤相比，TNBC在TNBC中植入率最高，与新诊断的原发性肿瘤相比（P = 0.024）。源自TNBC病例的PDX肿瘤表明小鼠肿瘤生长更快。基因表达分析表明，参与肿瘤 - 免疫相互作用的基因的下调与成功的PDX植入显着相关。植入基因签名与在TNBC病例的公开的mRNA数据集中测试时的存活结果较差。在植入相关的基因中，PHLDA2，TKT和P4HA2显示出三阴性乳腺癌细胞系中的高表达，并且基于siRNA的基因沉默导致体外细胞侵袭和增殖降低。我们的研究结果表明，PDX植入可以反映乳腺癌中的侵袭性表型。与PDX植入相关的基因可以在TNBC提供新的预后生物标志物和治疗靶标。

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