Regulation of Breast Cancer-induced Bone Lesions by β-Catenin Protein Signaling
Regulation of Breast Cancer-induced Bone Lesions by β-Catenin Protein Signaling
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DOI：
10.1074/jbc.m111.294595
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发表时间：
2011-12-09
影响因子：
4.8
通讯作者：
Zhang, Ming
中科院分区：
文献类型：
--
作者：
Chen, Yan;Shi, Heidi Y.;Zhang, Ming
乳腺癌患者骨转移率极高。对大多数患者骨骼的形态学分析揭示了混合性骨病变，包括溶骨成分和成骨细胞成分。 β-连环蛋白在胚胎骨骼发生和出生后骨再生中发挥着关键作用。尽管该通路也涉及许多骨恶性肿瘤，例如骨肉瘤和前列腺癌引起的骨转移，但其对乳腺癌骨转移的调节作用仍不清楚。在这里，我们提供的证据表明β-连环蛋白信号通路对骨病变表型具有显着影响。在这项研究中，我们通过胫骨内注射TM40D-MB细胞（一种高度骨转移的乳腺癌细胞系）建立了一种新型混合骨病变小鼠模型。我们发现，与非骨转移性TM40D细胞相比，TM40D-MB细胞中β-连环蛋白通路的上游和下游分子均上调。 TM40D-MB 细胞还具有比 TM40D 细胞更高的 T 细胞因子 (TCF) 报告活性。通过显性失活TCF4的表达使TM40D-MB细胞中的β-连环蛋白失活，不仅增加肿瘤骨共培养系统中的破骨细胞分化，增强小鼠的溶骨性骨破坏，而且抑制成骨细胞分化。令人惊讶的是，尽管过度表达β-连环蛋白的肿瘤细胞确实在体外诱导了成骨细胞分化的轻微增加，但这些细胞对小鼠成骨细胞骨形成的影响很小。这些数据共同表明，β-连环蛋白在混合骨病变中起着重要的决定因素的作用，特别是在控制肿瘤骨环境中的成骨细胞作用方面。
Breast cancer patients have an extremely high rate of bone metastases. Morphological analyses of the bones in most of the patients have revealed the mixed bone lesions, comprising both osteolytic and osteoblastic elements. beta-Catenin plays a key role in both embryonic skeletogenesis and postnatal bone regeneration. Although this pathway is also involved in many bone malignancy, such as osteosarcoma and prostate cancer-induced bone metastases, its regulation of breast cancer bone metastases remains unknown. Here, we provide evidence that the beta-catenin signaling pathway has a significant impact on the bone lesion phenotype. In this study, we established a novel mouse model of mixed bone lesions using intratibial injection of TM40D-MB cells, a breast cancer cell line that is highly metastatic to bone. We found that both upstream and downstream molecules of the beta-catenin pathway are up-regulated in TM40D-MB cells compared with non-bone metastatic TM40D cells. TM40D-MB cells also have a higher T cell factor (TCF) reporter activity than TM40D cells. Inactivation of beta-catenin in TM40D-MB cells through expression of a dominant negative TCF4 not only increases osteoclast differentiation in a tumor-bone co-culture system and enhances osteolytic bone destruction in mice, but also inhibits osteoblast differentiation. Surprisingly, although tumor cells overexpressing beta-catenin did induce a slight increase of osteoblast differentiation in vitro, these cells display a minimal effect on osteoblastic bone formation in mice. These data collectively demonstrate that beta-catenin acts as an important determinant in mixed bone lesions, especially in controlling osteoblastic effect within tumor-harboring bone environment.