Bone
pain is a common complication of
breast cancer (BC) bone
metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone
pain (
BCABP) remains poorly understood, involvement of BC products in the pathophysiology of
BCABP has been proposed. Aggressive
cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (
HMGB1), which acts as a
ligand for the
receptor for advanced glycation end products (RAGE) and
toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular
pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced
BCABP as evaluated by hind-paw mechanical
hypersensitivity. Importantly, silencing
HMGB1 in 4T1 BC cells by
shRNA reduced pERK and pCREB and
BCABP with decreased
HMGB1 levels in bone. Further, administration of a
neutralizing antibody to
HMGB1 or an antagonist for RAGE,
FPS-ZM1, ameliorated pERK, pCREB and
BCABP, while a TLR4 antagonist,
TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by
HMGB1 antibody. Our results show that
HMGB1 secreted by BC cells induces
BCABP via binding to RAGE of sensory neurons and suggest that the
HMGB1/RAGE axis may be a potential novel therapeutic target for
BCABP.