14-3-3zeta overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival.
14-3-3zeta overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival.
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DOI：
10.1158/0008-5472.can-08-2765
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Neal CL;Yao J;Yang W;Zhou X;Nguyen NT;Lu J;Danes CG;Guo H;Lan KH;Ensor J;Hittelman W;Hung MC;Yu D
14-3-3蛋白的普遍表达与许多重要的细胞功能有关。14-3-3σ的丢失是乳腺癌的常见事件；然而，其他14-3-3在乳腺癌中的作用尚不清楚。最近，我们发现14-3-3ζ过表达发生在早期乳腺疾病中，并有助于人类乳腺上皮细胞的转化。在这里，我们发现14-3-3ζ过表达在浸润性导管癌中也持续存在，并促进了乳腺癌的进一步进展。为了检验14-3-3ζ过表达在晚期乳腺癌中的临床影响，我们对原发性乳腺癌中的14-3-3ζ表达进行了免疫组织化学分析。14-3-3ζ过表达发生在42%的乳腺肿瘤中，并被确定为降低无病生存率的独立预后因素。14-3-3ζ过表达、ErbB2过表达和淋巴结状态阳性确定了发生远处转移的高风险患者亚组。为了研究14-3-3ζ的过表达是否会导致乳腺癌的进展，我们在癌细胞系中通过稳定转染过表达14-3-3ζ或通过siRNA降低14-3-3ζ的表达。14-3-3ζ表达增加可促进锚定独立生长，抑制应激诱导的细胞凋亡，而14-3-3ζ表达下调可降低锚定独立生长，并通过线粒体凋亡途径使细胞对应激诱导的细胞凋亡敏感。通过siRNA在癌细胞中短暂阻断14-3-3ζ的表达，可有效降低肿瘤异种移植物在体内的发生和生长。因此，14-3-3ζ过表达是乳腺癌患者疾病复发的一个新的分子标志物，可能作为肿瘤过表达14-3-3ζ的患者的有效治疗靶点。
The ubiquitously expressed 14-3-3 proteins are involved in numerous important cellular functions. The loss of 14-3-3σ is a common event in breast cancer; however, the role of other 14-3-3s in breast cancer is unclear. Recently, we found that 14-3-3ζ overexpression occurs in early stage breast diseases and contributes to transformation of human mammary epithelial cells. Here, we show that 14-3-3ζ overexpression also persisted in invasive ductal carcinoma and contributed to the further progression of breast cancer. To examine the clinical impact of 14-3-3ζ overexpression in advanced stage breast cancer, we performed immunohistochemical analysis of 14-3-3ζ expression in primary breast carcinomas. 14-3-3ζ overexpression occurred in 42% of breast tumors and was determined to be an independent prognostic factor for reduced disease-free survival. 14-3-3ζ overexpression combined with ErbB2 overexpression and positive lymph node status identified a subgroup of patients at high risk for developing distant metastasis. To investigate whether 14-3-3ζ overexpression causally promotes breast cancer progression, we overexpressed 14-3-3ζ by stable transfection or reduced 14-3-3ζ expression by siRNA in cancer cell lines. Increased 14-3-3ζ expression enhanced anchorage independent growth and inhibited stress-induced apoptosis, whereas downregulation of 14-3-3ζ reduced anchorage independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. Transient blockade of 14-3-3ζ expression by siRNA in cancer cells effectively reduced the onset and growth of tumor xenografts in vivo. Therefore, 14-3-3ζ overexpression is a novel molecular marker for disease recurrence in breast cancer patients and may serve as an effective therapeutic target in patients whose tumors overexpress 14-3-3ζ.