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

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Abstract

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.

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Acknowledgments

The authors thank Professor Kee Ryeon Kang for advices and criticisms regarding this study design and result interpretation. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2005929), by the grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (A1220200), SNUH Research Fund 0320130430 (2013-0512), and by the grant of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277 and HI13C2148).

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    Authors and Affiliations

    1. Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744, Seoul, Korea

      Hyeong-Gon Moon, Tae-Kyung Yoo, Wonshik Han & Dong-Young Noh

    2. Laboratory of Breast Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

      Hyeong-Gon Moon, Jiwoo Lee, Minju Lee, Tae-Kyung Yoo, Wonshik Han & Dong-Young Noh

    3. Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

      Keunhee Oh, Myung Won Seo & Dong-Sup Lee

    4. Department of Surgery, Gyeongsang National University, Jinju, Korea

      Ju-Yeon Kim & Eun-Jung Jung

    5. College of Pharmacy, Sunchon National University, Suncheon, Korea

      Ae Kyung Park

    6. Department of Pathology, Seoul National University Hospital, Seoul, Korea

      Han Suk Ryu

    7. Epigenomics Research Center, Genome Institute, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea

      Namshin Kim & Seongmun Jeong

    8. Department of Biomedical Sciences, Laboratory of Immunology and Cancer Biology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744, Seoul, Korea

      Dong-Sup Lee

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    Correspondence to Dong-Sup Lee or Dong-Young Noh.

    Additional information

    Hyeong-Gon Moon and Keunhee Oh have contributed equally to this article.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary Fig. 1

    Xenograft tumor growth in the consecutive transplanted cases in 7 cases. Supplementary material 1 (EPS 346 kb)

    Supplementary Fig. 2

    Quantitative analysis of cell invasion assay. Supplementary material 2 (EPS 556 kb)

    Supplementary Table 1

    Differentially expressed genes associated with the successful engraftment in patient-derived xenograft models. Supplementary material 3 (PDF 56 kb)

    Supplementary Table 2

    Significant gene ontology terms related to the up-regulated genes in tumors showing successful engraftment. Supplementary material 4 (PDF 51 kb)

    Supplementary Table 3

    Significant gene ontology terms related to the down-regulated genes in tumors showing successful engraftment. Supplementary material 5 (PDF 115 kb)

    Supplementary material 6 (DOCX 87 kb)

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    Moon, HG., Oh, K., Lee, J. et al. Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers. Breast Cancer Res Treat 154, 13–22 (2015). https://doi.org/10.1007/s10549-015-3585-y

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