14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation.
14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation.
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DOI：
10.1158/0008-5472.can-13-2016
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发表时间：
2014-01-01
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：
Rehman SK;Li SH;Wyszomierski SL;Wang Q;Li P;Sahin O;Xiao Y;Zhang S;Xiong Y;Yang J;Wang H;Guo H;Zhang JD;Medina D;Muller WJ;Yu D
14-3-3 β在超过40%的乳腺癌中过表达，但其与肿瘤发生的病理生理学相关性尚未确定。在这里，我们表明，14-3-3过表达足以诱导转基因小鼠乳腺癌模型中的肿瘤发生。MMTV-LTR启动子驱动的HA-14-3-3 β转基因小鼠（MMTV-HA-14-3-3 β）发生乳腺肿瘤，而对照小鼠则没有。乳清酸性蛋白启动子驱动的HA-14-3-3 β转基因小鼠（WAP-HA-14-3-3 β）出现增生性病变，并显示对致癌物诱导的肿瘤发生的易感性增加。当与MMTV-neu转基因小鼠杂交时，与MMTV-neu小鼠相比，14-3-3 α.neu转基因小鼠表现出加速的乳腺肿瘤发生和转移。从机制上讲，14-3-3 β过表达增强了MAPK/c-Jun信号传导，导致miR-221转录增加，这抑制了p27 CDKI翻译，因此促进了细胞增殖。重要的是，这种14-3-3 miR-221/p27/增殖轴也在患者的乳腺肿瘤中发挥作用，并与高级别癌症相关。综上所述，我们的研究结果表明，14-3-3 miR过表达在乳腺肿瘤发生和进展中具有因果作用，通过miR-221与已知的致癌事件合作来驱动肿瘤细胞增殖。
14-3-3ζ is overexpressed in over 40% of breast cancers but its pathophysiological relevance to tumorigenesis has not been established. Here we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors whereas control mice did not. Whey acidic protein promoter driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared to MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 CDKI translation, and consequently, promoted cell proliferation. Importantly, this 14-3-3ζ/miR-221/p27/proliferation axis is also functioning in patients' breast tumors and associates with high grade cancers. Taken together, our findings show that 14-3-3ζ overexpression has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.