The IKK/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 IKK/FoxO3a axis in bone metastasis. We found that IKK was highly expressed in invasive human breast tumours and that levels of expression were elevated in bone metastasis. Overexpression of IKK 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 IKK were inhibitory. Inhibition of IKK 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 IK contributes significantly to the regulation of tumour growth and osteolysis in breast cancer by NFKB dependent and independent mechanisms.

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Marino S, Bishop RT, Capulli M, Sophocleous A, Logan JG, Mollat P, Mognetti B, Ventura L, Sims AH, Rucci N, Ralston SH, Idris AI