Breast cancer commonly causes osteolytic
metastases in bone, a process that is dependent on
tumor-stromal interaction.
Proteases play an important role in modulating
tumor-stromal interactions in a manner that favors
tumor establishment and progression. Whereas several studies have examined the role of
proteases in modulating the bone microenvironment, little is currently known about their role in
tumor-bone interaction during osteolytic
metastasis. In
cancer-induced osteolytic lesions, cleavage of
receptor activator of nuclear factor-kappaB ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with
breast cancer-induced bone
metastases, we identified
cathepsin G,
cathepsin K,
matrix metalloproteinase (MMP)-9, and MMP13 to be
proteases that are up-regulated at the
tumor-bone interface using comparative
cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that
cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of
cathepsin G at the
tumor-bone interface seems to be osteoclasts that up-regulate production of
cathepsin G via interaction with
tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of
cathepsin G in a coculture model and that in vivo inhibition of
cathepsin G reduces mammary
tumor-induced
osteolysis. Together, our data indicate that
cathepsin G activity at the
tumor-bone interface plays an important role in mammary
tumor-induced
osteolysis and suggest that
cathepsin G is a potentially novel therapeutic target in the treatment of
breast cancer bone
metastasis.