title: NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF.
abstract: 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.
authors.affiliation: Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
authors.forename: Bae Keun
authors.initials: BK
authors.lastname: Park
authors.forename: Honglai
authors.initials: H
authors.lastname: Zhang
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Thomas
authors.initials: T
authors.lastname: Giordano
authors.forename: Keni
authors.initials: K
authors.lastname: Gu
authors.forename: Veena
authors.initials: V
authors.lastname: Shah
authors.forename: Lei
authors.initials: L
authors.lastname: Pei
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Zarbo
authors.forename: Laurie
authors.initials: L
authors.lastname: McCauley
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.forename: Shaoqiong
authors.initials: S
authors.lastname: Chen
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000139:chemically induced* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D016328:NF-kappa B; D016178:Granulocyte-Macrophage Colony-Stimulating Factor