Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response Public Deposited

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Creator
  • Wennemers, Marloes
    • Other Affiliation: Department of Laboratory Medicine, Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Nagtegaal, Iris D
    • Other Affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Varia, Mahesh A
    • Affiliation: School of Medicine, Department of Radiation Oncology
  • Bussink, Johan
    • Other Affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Scheijen, Blanca
    • Other Affiliation: Department of Pediatrics, Laboratory of Pediatric Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Raleigh, James A
    • Affiliation: School of Medicine, Department of Radiation Oncology
  • Rouschop, Kasper M
    • Other Affiliation: Maastricht Radiation Oncology (MaastRo) Lab, GROW-School for Oncology and Developmental Biology, University of Maastricht, PO box 616, 6200 AP Maastricht, The Netherlands
  • Span, Paul N
    • Other Affiliation: Department of Laboratory Medicine, Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Heuvel, Joop JTM
    • Other Affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • van Laarhoven, Hanneke WM
    • Other Affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  • Sweep, Fred CGJ
    • Other Affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Abstract
  • Abstract Introduction Hypoxia in solid tumors is associated with treatment resistance, resulting in poor prognosis. Tribbles homolog 3 (TRIB3) is induced during hypoxia and is involved in multiple cellular pathways involved in cell survival. Here, we investigated the role of TRIB3 in breast cancer. Methods TRIB3 mRNA expression was measured in breast tumor tissue from 247 patients and correlated with clinicopathological parameters and clinical outcome. Furthermore, we studied TRIB3 expression regulation in cell lines, xenografts tissues and human breast cancer material using Reverse transcriptase, quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining. Finally, the effect of small interfering RNA (siRNA) mediated TRIB3 knockdown on hypoxia tolerance was assessed. Results Breast cancer patients with low, intermediate or high TRIB3 expression exhibited a mean disease free survival (DFS) of 80 (95% confidence interval [CI] = 74 to 86), 74 (CI = 67 to 81), and 63 (CI = 55 to 71) months respectively (P = .002, Mantel-Cox log-rank). The prognostic value of TRIB3 was limited to those patients that had received radiotherapy as part of their primary treatment (n = 179, P = .005) and remained statistically significant after correction for other clinicopathological parameters (DFS, Hazard Ratio = 1.90, CI = 1.17 to 3.08, P = .009). In breast cell lines TRIB3 expression was induced by hypoxia, nutrient starvation, and endoplasmic reticulum stress in an hypoxia inducible factor 1 (HIF-1) independent manner. TRIB3 induction after hypoxia did not increase with decreasing oxygen levels. In breast tumor xenografts and human breast cancer tissues TRIB3 co-localized with the hypoxic cell marker pimonidazole. The induction of TRIB3 by hypoxia was shown to be regulated via the PERK/ATF4/CHOP pathway of the unfolded protein response and knockdown of TRIB3 resulted in a dose-dependent increase in hypoxia sensitivity. Conclusions TRIB3 is independently associated with poor prognosis of breast cancer patients, possibly through its association with tumor cell hypoxia.
Date of publication
Identifier
  • doi:10.1186/bcr2934
  • 21864376
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Marloes Wennemers et al.; licensee BioMed Central Ltd.
License
Journal title
  • Breast Cancer Research
Journal volume
  • 13
Journal issue
  • 4
Page start
  • R82
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1465-5411
Bibliographic citation
  • Breast Cancer Research. 2011 Aug 24;13(4):R82
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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