Intermittent hypoxia induces proteasome-dependent down-regulation of estrogen receptor α in human breast carcinoma
Intermittent hypoxia induces proteasome-dependent down-regulation of estrogen receptor α in human breast carcinoma
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DOI：
10.1158/1078-0432.ccr-04-1235
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发表时间：
2004-12-15
影响因子：
11.5
通讯作者：
Watson, PH
中科院分区：
文献类型：
--
作者：
Cooper, C;Liu, GY;Watson, PH
目的：缺氧可能影响基因表达，促进恶性肿瘤，急性缺氧已被证明可以短暂抑制乳腺细胞系中雌激素受体（ER）-α的表达。然而，间歇性缺氧的影响，这可能是更普遍的乳腺癌，仍有待确定。实验设计：ER-α表达进行了评估，Western印迹和免疫组化在选定的队列中的51 ER-α阳性乳腺癌，在缺氧的标志物。还在MCF 7和ZR-75乳腺细胞系中确定了急性和间歇性缺氧对ER-α表达的影响，以及蛋白酶体抑制剂硼替佐米对蛋白酶体功能的作用。ER-et表达的区域性缺失发生在乳腺肿瘤中，并且始终存在于缺氧区域，该缺氧区域由坏死附近和缺氧诱导基因碳酸酐酶IX（CA-IX）的诱导所定义。和葡萄糖转运蛋白1（Glut-1）在原位癌（n = 29; P < 0.0001）和浸润癌（n = 20; P = 0.0001）中的表达。在MCF 7和ZR-75细胞中，ER-α通过急性缺氧短暂下调，并通过复氧迅速恢复。然而，间歇性的急性缺氧可导致ER-α的类似下调，其不归因于mRNA的减少，并且尽管再氧合长达14天，但在MCF 7细胞中持续存在。这种效应发生时，细胞活力没有变化，但对雌二醇的生长反应相应降低。然而，ER-α的表达可以恢复bortezastrium.Conclusions：间歇性缺氧可能会导致蛋白酶体功能的持续变化，可能有助于减少ER-α在乳腺肿瘤中的表达，从而减少反应和耐内分泌治疗的发展。
Purpose: Hypoxia may influence gene expression to promote malignancy, and acute hypoxia has been shown to transiently repress estrogen receptor (ER)-alpha expression in breast cell lines. However, the effect of intermittent hypoxia, which is likely more prevalent in breast cancers, remains to be determined.Experimental Design: ER-alpha expression was assessed by, Western blot and immunohistochemistry in a selected cohort of 51 ER-alpha-positive breast carcinomas, in relation to markers of hypoxia. The effect of acute and intermittent hypoxia on ER-alpha expression was also determined in MCF7 and ZR-75 breast cell lines, together with the role of proteasome function with the proteasome inhibitor bortezomib.Results: Regional loss of ER-et expression occurs in breast tumors and is consistently present in hypoxic regions defined by the proximity of necrosis and induction of hypoxia-induced genes carbonic anhydrase IX (CA-IX) and glucose transporter 1 (Glut-1), in both in situ (n = 29; P < 0.0001) and invasive (n = 20; P = 0.0001) carcinomas. In MCF7 and ZR-75 cells, ER-alpha is transiently down-regulated by acute hypoxia and rapidly restored by reoxygenation. However, intermittent, acute hypoxia can cause a similar down-regulation of ER-alpha that is not attributable to decreased mRNA and persists in MCF7 cells despite reoxygenation for up to 14 days. This effect occurs with no change in cell viability but a corresponding reduction in growth response to estradiol. However, ER-alpha expression can be restored by bortezomib.Conclusions: Intermittent hypoxia can cause persistent changes in proteasome function that may contribute to reduced ER-alpha expression in breast tumors and consequently to diminished response and development of resistance to endocrine therapy.