The IKKβ/FoxO3a axis regulates breast cancer tumorigenesis and bone metastasis

IKB Kinase beta (IKKB), a key component of the NFKB signalling pathway plays an important role in inflammation and cancer. Here we describe a previously unknown role of the IKKβ/FoxO3a axis in bone metastasis. We found that IKKβ was highly expressed in invasive human breast tumours and that levels of expression were elevated in bone metastasis. Overexpression of IKKβ in parental and bone-tropic human breast cancer cell-lines increased tumour volume, worsened cachexia, promoted osteolysis and increased mortality in adult mice whereas pharmacological inhibition and knockdown of IKKβ were inhibitory. Inhibition of IKKβ in breast cancer cell lines and bone cells stimulated bone formation and reduced tumour growth by a mechanism that was mediated in part, by cytoplasmic sequestering of FoxO3a independently of NFKB inhibition. We conclude that IKβ contributes significantly to the regulation of tumour growth and osteolysis in breast cancer by NFKB dependent and independent mechanisms. Human MDA-231 control (mock), IKKβ deficient (IKKB si) and p65NFKB deficient (p65 si) breast cancer cells were hybridised to HT-12 Beadarrays in triplicate

IKB激酶β（IKB Kinase beta, IKKβ）是NFKB信号通路的核心组分，在炎症与肿瘤发生过程中发挥关键调控作用。本研究首次揭示了IKKβ/叉头框转录因子O3a（FoxO3a）信号轴在骨转移中的全新功能。研究发现，IKKβ在侵袭性人类乳腺肿瘤中呈高表达状态，且在骨转移病灶中的表达水平进一步上调。在亲本及亲骨性人乳腺癌细胞系中过表达IKKβ，可导致成年小鼠肿瘤体积增大、恶病质加重、溶骨作用增强并提升死亡率；而通过药理学抑制或基因敲低IKKβ，则可显著逆转上述恶性表型。在乳腺癌细胞系与骨细胞中抑制IKKβ，可通过部分依赖FoxO3a胞质滞留、不依赖NFKB抑制的分子机制，促进骨形成并抑制肿瘤生长。本研究最终证实，IKKβ可通过NFKB依赖与非依赖两种途径，显著调控乳腺癌中的肿瘤生长与溶骨过程。本研究将人MDA-231对照（空载转染，"mock"）、IKKβ敲低（"IKKB si"）及p65NFKB敲低（"p65 si"）乳腺癌细胞进行三次重复的HT-12微珠芯片（HT-12 Beadarrays）杂交实验。