CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer.
CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer.
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DOI：
10.1158/0008-5472.can-12-0154
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发表时间：
2012-09-15
期刊：
影响因子：
11.2
通讯作者：
Kleer CG
中科院分区：
文献类型：
--
作者：
Pal A;Huang W;Li X;Toy KA;Nikolovska-Coleska Z;Kleer CG
CCN6 是一种细胞外基质蛋白，在乳腺癌中发挥肿瘤抑制功能，其表达下降是晚期疾病的一个特征。然而，其在乳腺癌转移中的作用和作用机制尚未确定。骨形态发生蛋白（BMP）构成TGF-β超家族的配体，是诱导上皮间质转化（EMT）、细胞侵袭和转移的多功能细胞因子。在这项研究中，我们确定了一个 CCN6-BMP4-TAK1 激酶信号通路，该通路控制 p38 MAP 激酶调节腺泡形态发生和乳腺细胞侵袭的能力。 ShRNA 介导的人乳腺上皮 (HME) 细胞中 CCN6 的减弱导致 BMP4 上调，这是暴露于 TGF-β 超家族的主要反应。 CCN6 减弱还诱导 BMP4 介导的不依赖于 Smad 的 TAK1 和 p38 激酶的激活。相反，乳腺癌细胞中CCN6的异位表达通过结合BMP4蛋白以及降低BMP4蛋白水平来拮抗BMP4介导的TAK1/p38激活和侵袭能力。对 BMP4 和 p38 的影响在体内得到证实，它们与转移减少相关。在临床样本中，我们发现在 69% 的浸润性乳腺癌检查中，CCN6 表达与 BMP4 和磷酸化 p38 水平呈负相关，这与功能结果一致。我们的研究结果共同确定了一种新的修饰途径，CCN6 通过该途径发挥限制乳腺癌侵袭和转移的作用。
CCN6 is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition (EMT), cell invasion and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial (HME) cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated TAK1/p38 activation and invasive capacity, both by binding BMP4 protein as well as decreasing BMP4 protein levels. Effects on BMP4 and p38 were confirmed in vivo where they correlated with decreased metastasis. In clinical specimens, we found that CCN6 expression was inversely associated with BMP4 and phospho-p38 levels in 69% of invasive breast carcinomas examined, consistent with the functional results. Together our findings identify a novel modifier pathway through which CCN6 acts to limit breast cancer invasion and metastasis.