Expression and splicing of the unfolded protein response gene XBP-1 are sieniticantly associated with clinical outcome of endocrine-treated breast cancer
Expression and splicing of the unfolded protein response gene XBP-1 are sieniticantly associated with clinical outcome of endocrine-treated breast cancer
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DOI：
10.1002/ijc.23479
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Sibson, David Ross
中科院分区：
文献类型：
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作者：
Davies, Michael P. A.;Barraclough, Dong Liu;Sibson, David Ross
X-box结合蛋白1 （XBP-1）作为未折叠蛋白反应（UPR）的一部分受到内质网应激刺激，可促进细胞凋亡或细胞存活。在UPR期间激发的非常规剪接将“未剪接”的XBP-1U mRNA转化为“剪接”的XBP-1S mRNA。XBP-1 mRNA对雌激素敏感，但XBP-1S对乳腺癌细胞系具有雌激素独立性和抗雌激素抗性。因此，我们评估了XBP-1 mRNA剪接作为乳腺癌患者对内分泌治疗反应的一个因素。采用定量RT-PCR方法对100例接受他莫昔芬辅助治疗的原发性乳腺癌患者（包括30例ER α阴性患者）的XBP-1亚型进行检测。在ER α阳性病例中，XBP-1U mRNA水平与ER α mRNA水平相关，并且在3级肿瘤中较低。高水平的XBP-1U mRNA与乳腺癌生存率显著相关（Log-rank p = 0.002； Cox风险比（HR） 0.2, p = 0.005），与分级、大小、淋巴结状态和孕激素受体状态无关。然而，在整个队列中，较高的XBP-1S/XBP-1U mRNA比例（表明剪接增强）与较差的生存率（Log-rank p = 0.03; Cox HR 2.3, p = 0.03）以及相关因素：ER α阴性状态、孕酮受体阴性状态、3级肿瘤和更大的增殖。在era阳性病例中，XBP-1剪接也与不良预后显著相关。我们的研究发现，XBP-1亚型与患者内分泌治疗的结果有不同的相关性，这可以解释为高水平的显性阴性XBP-1U有利于肿瘤细胞凋亡，高水平的XBP-1S增加肿瘤存活率。(C) 2008 Wiley-Liss, Inc。
X-box binding protein 1 (XBP-1) is stimulated by endoplasmic reticulum stress as part of the unfolded protein response (UPR), which can promote apoptosis or cell survival. Non-conventional splicing, stimulated during the UPR, converts mRNA for "unspliced" XBP-1U to "spliced" XBP-1S mRNA. XBP-1 mRNA is oestrogen-responsive, but XBP-1S confers oestrogen independence and anti-oestrogen resistance to breast cancer cell lines. We therefore evaluated XBP-1 mRNA splicing as a factor in response of breast cancer patients to endocrine treatment. XBP-1 isoforms were measured by quantitative RT-PCR in 100 primary breast cancer patients treated with adjuvant tamoxifen (including 30 ER alpha-negative cases). In ER alpha-positive cases, levels of XBP-1U mRNA correlated with ER alpha mRNA levels and were lower in grade 3 tumors. Higher levels of XBP-1U mRNA were significantly associated with breast cancer survival (Log-rank p = 0.002; Cox hazard ratio (HR) 0.2, p = 0.005), independent of grade, size, nodal status and progesterone receptor status. However, in the full cohort, higher ratios of XBP-1S/XBP-1U mRNA (indicating enhanced splicing) were associated with poor survival (Log-rank p = 0.03; Cox HR 2.3, p = 0.03) and related factors: ER alpha-negative status, progesterone receptor negative status, grade 3 tumors and greater proliferation. Significant associations with poor outcome were also seen for XBP-1 splicing in ERa-positive cases. Our findings, that XBP-1 isoforms are differently associated with outcome of endocrine therapy for patients, can be explained by higher levels of dominant-negative XBP-1U favouring apoptosis of tumor cells and higher levels of XBP-1S increasing tumor survival. (C) 2008 Wiley-Liss, Inc.