Abstract
IntroductionHypoxia 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.MethodsTRIB3 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.ResultsBreast 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.ConclusionsTRIB3 is independently associated with poor prognosis of breast cancer patients, possibly through its association with tumor cell hypoxia.
Highlights
Hypoxia in solid tumors is associated with treatment resistance, resulting in poor prognosis
When the patients were divided into three sized groups based on the level of Tribbles homolog 3 (TRIB3) mRNA in the primary tumor the group with the lowest amount of TRIB3 expression had a mean disease free survival (DFS) of 80 months (95% confidence interval (CI) = 74 to 86 months), whereas the group with an average amount of TRIB3 had a mean DFS of 74 months and the group with high levels of TRIB3 had a mean DFS of 63 months
Similar differences were found after division of the patients in two equal groups (DFS: hazard ratio (HR) = 2.15, 95% CI = 1.39 to 3.31, P < 0.001; overall survival (OS): HR = 3.48, 95% CI = 2.00 to 6.06, P < 0.001; Table 2), and when TRIB3 was entered as a continuous factor after log-normalization in a univariate Cox regression analysis
Summary
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. The accelerated growth and erratic angiogenesis of solid tumors induce a lack of oxygen and nutrients in parts of the tumor that are distal to functional blood vessels. This is known to have important repercussions for treatment sensitivity and prognosis of cancer patients [1,2,3]. TRIB3 has been described to have a role in the mitogen activated protein kinase (MAPK) pathway [11] and nuclear factor (NF) B activated apoptosis [7]. TRIB3 was shown to be upregulated compared with normal tissue in tumors of the human lung, colon, and breast [14,17,18]
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