Bone morphogenetic protein 7 in the development and treatment of bone Metastases from breast cancer
Bone morphogenetic protein 7 in the development and treatment of bone Metastases from breast cancer
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DOI：
10.1158/0008-5472.can-06-2490
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Van der Pluijm, Gabri
中科院分区：
文献类型：
--
作者：
Buijs, Jeroen T.;Henriquez, Nico V.;Van der Pluijm, Gabri
骨形态发生蛋白7（BMP7）可对抗生理性上皮 - 间质转化（EMT），这一过程体现了上皮的可塑性。由于EMT与癌症有关，我们研究了BMP7是否在乳腺癌的生长和转移中起作用。在本研究中，我们发现，在对患者进行2 - 10年的随访后，原发性乳腺癌中BMP7表达降低与临床明显的骨转移形成显著相关。与这些临床观察结果一致，BMP7的表达与人乳腺癌细胞系的致瘤性和侵袭行为呈负相关。此外，在基础条件和转化生长因子 - β（TGF - β）刺激条件下，BMP7降低了波形蛋白的表达，波形蛋白是一种与侵袭性和不良预后相关的间质标志物，在人MDA - MB - 231（MDA - 231） - B/Luc(+)乳腺癌细胞中。另外，在TGF - β刺激的MDA - 231细胞中外源添加BMP7可抑制Smad介导的TGF - β信号传导。此外，在一个使用全身生物发光报告成像的成熟骨转移模型中，MDA - 231细胞中BMP7的稳定过表达抑制了溶骨性骨转移的新生形成和进展，从而抑制了它们的转移能力。与这些观察结果一致，每日静脉注射BMP7（100μg/kg/d）可显著抑制裸鼠中MDA - 231 - B/Luc(+)细胞的原位和骨内生长。我们的数据表明，人乳腺癌变过程中BMP7表达降低有助于获得骨转移表型。由于外源BMP7仍可对抗原发性部位和骨中的乳腺癌生长，BMP7可能代表一种用于抑制乳腺癌局部和骨转移生长的新型治疗分子。
Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with 2 10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc(+) breast cancer cells under basal and transforming growth factor-beta (TGF-beta)-stimulated conditions. In addition, exogenous addition of BMP7 to TGF-beta-stimulated MDA-231 cells inhibited Smad-mediated TGF-beta signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 mu g/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc(+) cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer.