title: Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers.
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.
authors.affiliation: 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.
authors.forename: Hyeong-Gon
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.affiliation: Laboratory of Breast Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jiwoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Breast Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Minju
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Surgery, Gyeongsang National University, Jinju, Korea.
authors.forename: Ju-Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Yoo
authors.affiliation: Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Myung Won
authors.initials: MW
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Sunchon National University, Suncheon, Korea.
authors.forename: Ae Kyung
authors.initials: AK
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Han Suk
authors.initials: HS
authors.lastname: Ryu
authors.affiliation: Department of Surgery, Gyeongsang National University, Jinju, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Jung
authors.affiliation: Epigenomics Research Center, Genome Institute, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: Namshin
authors.initials: N
authors.lastname: Kim
authors.affiliation: Epigenomics Research Center, Genome Institute, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
authors.forename: Seongmun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: 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.
authors.forename: Wonshik
authors.initials: W
authors.lastname: Han
authors.affiliation: Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. dlee5522@snu.ac.kr.|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. dlee5522@snu.ac.kr.
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744, Seoul, Korea. dynoh@snu.ac.kr.|Laboratory of Breast Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. dynoh@snu.ac.kr.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D064828:Prolyl Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009687:Nuclear Proteins; C109277:TSSC3 protein; C000591164:P4HA2 protein, human; D064828:Prolyl Hydroxylases
keywords: Breast cancer; Engraftment; Patient-derived xenograft; Prognosis; Triple-negative breast cancer