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

Contains fulltext : 96483.pdf (publisher's version ) (Open Access)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

Hypoxia in a human intracerebral glioma model

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Hypoxia regulation of phosphokinases and the prognostic value of pAKT in breast cancer

Item does not contain fulltextTumor hypoxia results in poor treatment response and is an indicator of poor outcome in cancer patients. TRIB3 is a hypoxia-upregulated protein involved in the ability of breast cancer cells to survive in hypoxic conditions. It is also involved in the prognosis of cancer patients, possibly by affecting several kinase-signaling pathways. We set out to establish which kinase-signaling pathways are regulated by hypoxia and whether these kinases are relevant for breast cancer prognosis. Using a phosphokinase antibody array comparing cells cultured under hypoxic conditions with those cultured during normoxia, we found that the phosphorylation status of ERK1/2, AKT, p70 S6 kinase, Lck and STAT3 was altered in both MCF7 and MDA-MB-231 breast cancer cells. Using Western blotting, we found that phosphorylated AKT (pAKT) increased in hypoxic conditions. Knockdown of TRIB3 attenuated this effect of hypoxia on AKT activation. Both pAKT and TRIB3 were expressed in pimonidazole-positive, hypoxic areas of human breast cancer tumors. In breast cancer patients significantly lower 5-year disease-free survival was observed for the pAKT-positive compared to the pAKT-negative group (64.6% vs 86.1%, p=0.03). In conclusion, the phosphorylation status of AKT is increased in hypoxic conditions and TRIB3 knockdown attenuates this response. Furthermore, pAKT expression denotes a worse prognosis in breast cancer patients. The hypoxia-related activation of AKT could explain the resistance to various treatments including chemotherapy and radiotherapy