Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway
Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway
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DOI：
10.1073/pnas.0506517102
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发表时间：
2005-09-27
影响因子：
11.1
通讯作者：
Massagué, J
中科院分区：
文献类型：
--
作者：
Kang, YB;He, W;Massagué, J
TGF-β可以通过Smad转录因子（其是抑制细胞增殖的典型肿瘤抑制因子）和通过与肿瘤进展有关的Smad非依赖性机制发出信号。尽管Smad突变在某些癌症中使这种肿瘤抑制途径失效，但乳腺癌细胞经常逃避TGF-β的细胞生长抑制作用，同时保留Smad功能。通过免疫组化分析人乳腺癌骨转移和功能成像的Smad通路在小鼠异种移植模型，我们提供的证据，在人类和小鼠骨转移病变的活性Smad信号。遗传耗竭实验进一步证明，Smad 4有助于溶骨性骨转移的形成，并且对于诱导IL-11（在该小鼠模型系统中与骨转移有关的基因）是必需的。激活蛋白-1是Smad依赖的IL-11转录激活及其在骨转移细胞中过表达的关键参与者。我们的研究结果提供了功能的证据，开关的Smad通路，从肿瘤抑制剂，促进转移，在乳腺癌骨转移的发展。
TGF-beta can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-beta while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bone-metastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.