Tribbles 同源物 3 表示乳腺癌预后不良，并参与缺氧反应。
Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response.
机构信息
Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
出版信息
Breast Cancer Res. 2011 Aug 24;13(4):R82. doi: 10.1186/bcr2934.
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.
简介
实体肿瘤中的缺氧与治疗抵抗有关，导致预后不良。TRI bles 同源物 3（TRIB3）在缺氧时被诱导，并参与涉及细胞存活的多种细胞途径。在这里，我们研究了 TRIB3 在乳腺癌中的作用。
方法
在 247 例乳腺癌患者的肿瘤组织中测量 TRIB3mRNA 的表达，并将其与临床病理参数和临床结果相关联。此外，我们使用逆转录酶、定量聚合酶链反应（RT-qPCR）和免疫组织化学染色研究了细胞系、异种移植组织和人乳腺癌组织中 TRIB3 表达的调节。最后，评估了小干扰 RNA（siRNA）介导的 TRIB3 敲低对缺氧耐受性的影响。
结果
TRIB3 低、中或高表达的乳腺癌患者的无病生存（DFS）平均分别为 80（95%置信区间[CI] = 74 至 86）、74（CI = 67 至 81）和 63（CI = 55 至 71）个月（P =.002，Mantel-Cox 对数秩）。TRIB3 的预后价值仅限于接受放疗作为其主要治疗一部分的患者（n = 179，P =.005），并且在纠正其他临床病理参数后仍然具有统计学意义（DFS，风险比= 1.90，CI = 1.17 至 3.08，P =.009）。在乳腺癌细胞系中，TRIB3 表达被缺氧、营养饥饿和内质网应激以一种缺氧诱导因子 1（HIF-1）独立的方式诱导。缺氧后 TRIB3 的诱导并没有随着氧水平的降低而增加。在乳腺癌肿瘤异种移植和人乳腺癌组织中，TRIB3 与缺氧细胞标记物 pimonidazole 共定位。缺氧诱导的 TRIB3 被证明是通过未折叠蛋白反应的 PERK/ATF4/CHOP 途径调节的，TRIB3 的敲低导致缺氧敏感性呈剂量依赖性增加。
结论
TRIB3 与乳腺癌患者的不良预后独立相关，可能与其与肿瘤细胞缺氧有关。
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