Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway
Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway
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DOI：
10.1038/onc.2008.232
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发表时间：
2008-10-01
期刊：
影响因子：
8
通讯作者：
Imamura, T.
中科院分区：
文献类型：
--
作者：
Katsuno, Y.;Hanyu, A.;Imamura, T.
已知转化生长因子（TGF）-β促进肿瘤侵袭和转移。虽然骨形态发生蛋白（BMPs），TGF-β家族的成员，在多种人类癌细胞系中表达，但其在肿瘤进展中的作用尚未完全阐明。在这项研究中，我们试图确定骨形成蛋白在乳腺癌骨转移的进展中的作用，使用人乳腺癌样本和小鼠异种移植模型。来自乳腺癌患者的样品以及MDA-231-D（高转移性人乳腺癌细胞）的小鼠异种移植物模型的免疫组织化学分析揭示了原发性肿瘤和/或骨转移中癌细胞核中的磷酸化Smad 2和磷酸化Smad 1/5/8染色。使用功能性体内生物发光成像系统，我们发现TGF-β和BMP诱导的转录途径在体内骨转移病灶中是活跃的。此外，TGF-β 3和BMP-2在体外均促进MDA-231-D细胞的运动性和侵袭性。此外，MDA-231-D细胞中TGF-β和/或BMP的显性负性受体的表达抑制了体外侵袭和异种移植模型中的骨转移。这些结果表明，BMP和TGF-β促进乳腺癌的侵袭和骨转移。
Transforming growth factor (TGF)-beta is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins ( BMPs), members of the TGF-beta family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-beta- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-beta 3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-beta and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-beta promote invasion and bone metastasis of breast cancer.