Smad-binding defective mutant of transforming growth factor β type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines
Smad-binding defective mutant of transforming growth factor β type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines
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DOI：
10.1158/0008-5472.can-04-0030
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发表时间：
2004-07-01
期刊：
影响因子：
11.2
通讯作者：
Roberts, AB
中科院分区：
文献类型：
--
作者：
Tian, F;Byfield, SD;Roberts, AB
转化生长因子β在肿瘤发生中的作用是复杂的，肿瘤抑制和促肿瘤活性取决于特定的肿瘤细胞及其恶性进展阶段。我们以前已经在乳腺癌细胞系中证明，Smad2/3信号在介导作为异种移植生长的高分化乳腺癌细胞系的肿瘤抑制效应和在更具侵袭性、更转移的细胞系的前转移效应中起主导作用。我们目前的数据基于选择性干扰通过稳定表达不能结合Smad2/3但再次与功能激酶结合的突变形式的转化生长因子-βI型受体(RImL45)来激活内源性Smad2和Smad3，表明RImL45的表达减少了Smad2/3信号的表达，增强了高分化MCF10A来源的肿瘤细胞系MCF10CA1h移植瘤的恶性程度，导致形成更大的肿瘤，具有更高的增殖指数和更多的恶性组织学特征。相反，RImL45在更具侵袭性的MCF10CA1a细胞系中的表达强烈抑制了尾静脉注射后肺转移的形成。这些结果表明，内源性Smad2/3信号通路在这些细胞中转化生长因子-β的肿瘤抑制和促转移活性中起主导作用。通过体外实验，我们进一步证明了非Smad信号通路，包括p38和c-jun NH2末端激酶，与转化生长因子-β/Smads协同促进转移性MCF10CA1a细胞的迁移，但这些其他途径虽然是迁移所必需的，但不足以促进转移。
The role of transforming growth factor beta (TGF-beta) in carcinogenesis is complex, with tumor suppressor and pro-oncogenic activities depending on the particular tumor cell and its stage in malignant progression. We previously have demonstrated in breast cancer cell lines that Smad2/3 signaling played a dominant role in mediating tumor suppressor effects on well-differentiated breast cancer cell lines grown as xenografts and prometastatic effects on a more invasive, metastatic cell line. Our present data based on selective interference with activation of endogenous Smad2 and Smad3 by stable expression of a mutant form of the TGF-beta type I receptor (RImL45) unable to bind Smad2/3 but with a functional kinase again show that reduction in Smad2/3 signaling by expression of RImL45 enhanced the malignancy of xenografted tumors of the well-differentiated MCF10A-derived tumor cell line MCF10CA1h, resulting in formation of larger tumors with a higher proliferative index and more malignant histologic features. In contrast, expression of RImL45 in the more aggressive MCF10CA1a cell line strongly suppressed formation of lung metastases following tail vein injection. These results suggest a causal, dominant role for the endogenous; Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-beta in these cells. Using an in vitro assay, we further show that non-Smad signaling pathways, including p38 and c-Jun NH2-terminal kinase, cooperate with TGF-beta/Smads in enhancing migration of metastatic MCF10CA1a cells, but that, although necessary for migration, these other pathways are not sufficient for metastasis.