Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers

被引:51
作者
Moon, Hyeong-Gon [1 ,2 ]
Oh, Keunhee [3 ]
Lee, Jiwoo [2 ]
Lee, Minju [2 ]
Kim, Ju-Yeon [4 ]
Yoo, Tae-Kyung [1 ,2 ]
Seo, Myung Won [3 ]
Park, Ae Kyung [5 ]
Ryu, Han Suk [6 ]
Jung, Eun-Jung [4 ]
Kim, Namshin [7 ]
Jeong, Seongmun [7 ]
Han, Wonshik [1 ,2 ]
Lee, Dong-Sup [3 ,8 ]
Noh, Dong-Young [1 ,2 ]
机构
[1] Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110744, South Korea
[2] Seoul Natl Univ, Coll Med, Canc Res Inst, Lab Breast Canc Biol, Seoul 110744, South Korea
[3] Seoul Natl Univ, Canc Res Inst, Coll Med, Lab Immunol,Interdisciplinary Program Tumor Biol, Seoul, South Korea
[4] Gyeongsang Natl Univ, Dept Surg, Jinju, South Korea
[5] Sunchon Natl Univ, Coll Pharm, Sunchon, South Korea
[6] Seoul Natl Univ Hosp, Dept Pathol, Seoul 110744, South Korea
[7] Korea Res Inst Biosci & Biotechnol, Genome Inst, Epigenom Res Ctr, Taejon, South Korea
[8] Seoul Natl Univ, Coll Med, Lab Immunol & Canc Biol, Dept Biomed Sci, Seoul 110744, South Korea
基金
新加坡国家研究基金会;
关键词
Breast cancer; Patient-derived xenograft; Engraftment; Prognosis; Triple-negative breast cancer; SUBTYPES; METASTASIS; THERAPY; GROWTH;
D O I
10.1007/s10549-015-3585-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
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.
引用
收藏
页码:13 / 22
页数:10
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