Moon Hyeong-Gon, Oh Keunhee, Lee Jiwoo, Lee Minju, Kim Ju-Yeon, Yoo Tae-Kyung, Seo Myung Won, Park Ae Kyung, Ryu Han Suk, Jung Eun-Jung, Kim Namshin, Jeong Seongmun, Han Wonshik, Lee Dong-Sup, Noh Dong-Young
Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744, Seoul, Korea.
Laboratory of Breast Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Breast Cancer Res Treat. 2015 Nov;154(1):13-22. doi: 10.1007/s10549-015-3585-y. Epub 2015 Oct 5.
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.
我们旨在确定影响乳腺癌患者来源异种移植（PDX）模型中肿瘤成功植入的因素。此外，我们研究了PDX植入相关基因在三阴性乳腺癌（TNBC）中的预后意义和功能重要性。分析了81例乳腺癌患者的临床病理特征，这些患者的组织用于PDX移植，以确定影响PDX植入的因素。发现了一个与PDX植入相关的基因特征，并在公开可用的数据集中和体外试验中测试了其临床重要性。81个移植肿瘤中有19个（23.4%）成功植入PDX模型。与其他亚型相比，TNBC的植入率最高（p = 0.001），与新诊断的原发性肿瘤相比，复发或化疗耐药肿瘤的植入率最高（p = 0.024）。源自TNBC病例的PDX肿瘤在小鼠中显示出更快的肿瘤生长。基因表达谱分析表明，参与肿瘤免疫相互作用的基因下调与PDX成功植入显著相关。在TNBC病例的公开可用mRNA数据集中测试时，植入基因特征与较差的生存结果相关。在与植入相关的基因中，PHLDA2、TKT和P4HA2在三阴性乳腺癌细胞系中高表达，基于siRNA的基因沉默导致体外细胞侵袭和增殖减少。我们的结果表明，PDX植入可能反映了乳腺癌的侵袭性表型。与PDX植入相关的基因可能为TNBC提供一种新的预后生物标志物和治疗靶点。
