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

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. Overall design: 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