Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response
| Autor: | Blanca Scheijen, James A. Raleigh, Johan Bussink, Fred C.G.J. Sweep, Hanneke W. M. van Laarhoven, Paul N. Span, J. J. T. M. Heuvel, Mahesh A. Varia, Marloes Wennemers, Kasper M.A. Rouschop, Iris D. Nagtegaal |
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| Přispěvatelé: | Oncology, Radiotherapie, RS: GROW - School for Oncology and Reproduction |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adult
medicine.medical_treatment Mice Nude Breast Neoplasms Cell Cycle Proteins Protein Serine-Threonine Kinases CHOP Biology Disease-Free Survival Mice eIF-2 Kinase Breast cancer Surgical oncology Cell Line Tumor medicine Animals Humans RNA Small Interfering Aged Aged 80 and over Medicine(all) Gene knockdown Middle Aged Hypoxia (medical) Endoplasmic Reticulum Stress Hypoxia-Inducible Factor 1 alpha Subunit Prognosis medicine.disease Activating Transcription Factor 4 Xenograft Model Antitumor Assays Molecular biology Cell Hypoxia Gene Expression Regulation Neoplastic Repressor Proteins Radiation therapy Real-time polymerase chain reaction TRIB3 Gene Knockdown Techniques Cancer research Female medicine.symptom Transcription Factor CHOP Research Article |
| Zdroj: | Breast cancer research, 13(4). BioMed Central Breast Cancer Research : BCR Breast Cancer Research, 13(4). BioMed Central Ltd |
| ISSN: | 1465-5411 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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