Park Bae Keun, Zhang Honglai, Zeng Qinghua, Dai Jinlu, Keller Evan T, Giordano Thomas, Gu Keni, Shah Veena, Pei Lei, Zarbo Richard J, McCauley Laurie, Shi Songtao, Chen Shaoqiong, Wang Cun-Yu
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
Nat Med. 2007 Jan;13(1):62-9. doi: 10.1038/nm1519. Epub 2006 Dec 10.
Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.
晚期乳腺癌常转移至骨骼，导致溶骨性病变，但其潜在机制尚不清楚。在此我们报告，核因子-κB（NF-κB）通过刺激破骨细胞生成，在乳腺癌的溶骨性骨转移中起关键作用。利用体内骨转移模型，我们发现乳腺癌细胞中组成型NF-κB活性对于溶骨性骨转移的骨吸收特征至关重要。我们确定编码粒细胞巨噬细胞集落刺激因子（GM-CSF）的基因是NF-κB的关键靶点，并发现它通过刺激破骨细胞发育介导乳腺癌的溶骨性骨转移。此外，我们观察到GM-CSF的表达与乳腺癌患者骨转移肿瘤组织中的NF-κB激活相关。这些结果揭示了NF-κB通过诱导GM-CSF在溶骨性骨转移中的新的特定作用，表明NF-κB是治疗乳腺癌和预防骨转移的潜在靶点。
