IκB Kinase β (IKKβ), a key component of NFκB signaling, plays an important role in bone disease and cancer. Genetic and pharmacological inhibition of IKKβ/NFκB signaling increase bone mass and protect against ovariectomy- and inflammation-induced bone loss. Here, we describe a previously unknown role of the IKKβ/FoxO3a axis in bone metastasis associated with breast cancer. We observed that IKKβ expression is prevalent in invasive breast cancer carcinoma and significantly elevated in bone metastasis specimens from the same breast cancer patients. Overexpression of IKKβ (ninefold increase) in the human breast cancer cells MDA-MB-231 (MDA-231) significantly worsened cachexia (40% increase) and mortality (50% increase) and exacerbated bone metastasis (25% increase) after intracardiac injection, enhanced tumour volume (60% increase) after orthotopic injection and provoked osteolysis (30% loss of bone volume) after supracalvarial injection of conditioned medium from these cells. Conversely, pharmacological inhibition and selective knockdown of IKKβ in MDA-231 cells inhibited cell migration (69% reduction), significantly reduced the ability of MDA-231 cells to induce osteoclast formation (87% reduction), to enhance osteoblasts support for osteoclastogenesis (75% reduction) and to reduce osteoblast differentiation in vitro (29% increase), and to cause osteolysis in vivo (27% gain in bone volume). An integrative analytic approach that utilizes data from co-culture systems, western blot analysis and gene expression microarrays revealed that disruption of IKKβ interaction with the pro-apoptotic transcription factor FoxO3a, but not NFκB, increases FoxO3a nuclear localisation (10% increase) that alter the balance of tumour derived osteolytic (IL8, VEGF, ADM and CXCL16) and pro-osteoblastic (BMP4 and WNT7B) secreted factors, thereby favouring osteoblast differentiation over osteoclast formation. In conclusion, we demonstrate that the IKKβ/FoxO3a axis serves as a common target that regulate cancer cell osteoblast osteoclast paracrine crosstalk in bone metastatic environment, and inhibition of IKKβ-FoxO3a interaction protects against bone metastasis and encourages bone formation.
17 May 2014 - 20 May 2014