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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.
AuthorsHyeong-Gon Moon, Keunhee Oh, Jiwoo Lee, Minju Lee, Ju-Yeon Kim, Tae-Kyung Yoo, Myung Won Seo, Ae Kyung Park, Han Suk Ryu, Eun-Jung Jung, Namshin Kim, Seongmun Jeong, Wonshik Han, Dong-Sup Lee, Dong-Young Noh
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 154 Issue 1 Pg. 13-22 (Nov 2015) ISSN: 1573-7217 [Electronic] Netherlands
PMID26438141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Nuclear Proteins
  • TSSC3 protein
  • P4HA2 protein, human
  • Prolyl Hydroxylases
Topics
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation (genetics)
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Nuclear Proteins (biosynthesis, genetics)
  • Prognosis
  • Prolyl Hydroxylases (biosynthesis, genetics)
  • Triple Negative Breast Neoplasms (genetics, pathology)
  • Tumor Burden (genetics)
  • Xenograft Model Antitumor Assays

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