Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis.
Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis.
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DOI：
10.1038/cdd.2011.122
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发表时间：
2012-03
影响因子：
12.4
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中科院分区：
文献类型：
--
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在乳腺发育的不同阶段，需要通过JAK/STAT通路传递信号，而这一通路在癌症(包括乳腺肿瘤)中经常过度激活。STAT3、STAT5和STAT6在乳腺细胞的分化和存活中起重要作用，但有些矛盾的是，STAT3和STAT5在乳腺中都具有致癌活性。JAK2的结构性激活可以预期导致Stat1、Stat3、Stat5和Stat6的过度激活并伴随细胞转化，尽管结果很难想象，特别是因为Stat3和Stat5在正常乳腺发育中扮演着相反的角色。在这里，我们证明了具有结构性活性的JAK2突变体JAK2 V617F的表达导致乳腺上皮细胞(MECs)中Stat5的过度激活，并且在乳腺中特异性表达JAK2 V617F的转基因小鼠在怀孕期间表现出加速的肺泡形成和延迟的哺乳期后退化。在体外高表达JAK2 V617F的微血管内皮细胞可促进细胞增殖和抵抗细胞死亡。此外，在存在共同操作的癌基因的情况下，成分活性的JAK2增强了非锚定细胞的生长，并在异种移植模型中加速了肿瘤的发生。综上所述，我们的结果为深入了解成分活性JAK2的信号下游提供了见解，并可能对于理解乳腺肿瘤发生的分子机制很重要。
Signalling through the JAK/Stat pathway is required at different stages of mammary gland development and this pathway is frequently hyper-activated in cancer, including tumours of the breast. Stats 3, 5 and 6 have important roles in the differentiation and survival of mammary alveolar cells but somewhat paradoxically, both Stat3 and 5 can have oncogenic activity in the mammary gland. Constitutive activation of JAK2 could be anticipated to result in hyper-activation of Stats 1, 3, 5 and 6 with concomitant cell transformation although the outcome is difficult to envisage particularly since Stats 3 and 5 play opposing roles in normal mammary gland development. Here, we show that expression of a constitutively active JAK2 mutant, JAK2 V617F, leads to hyperactivation of Stat5 in mammary epithelial cells (MECs) and transgenic mice expressing JAK2 V617F specifically in the mammary gland exhibit accelerated alveologenesis during pregnancy and delayed post-lactational regression. Over-expressing JAK2 V617F in MECs in vitro resulted in elevated proliferation and resistance to cell death. Furthermore, constitutively active JAK2 enhances anchorage-independent cell growth in the presence of a co-operating oncogene and accelerates tumourigenesis in a xenograft model. Taken together, our results provide insights into signalling downstream of constitutively active JAK2 and could be important for understanding the molecular mechanisms of breast tumourigenesis.
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