Cathepsin B inhibition limits bone metastasis in breast cancer

Nimali P Withana, Galia Blum, Mansoureh Sameni, Clare Slaney, Arulselvi Anbalagan, Mary B Olive, Bradley N Bidwell, Laura Edgington, Ling Wang, Kamiar Moin, Bonnie F Sloane, Robin L Anderson, Matthew S Bogyo, Belinda S Parker

Research output: Contribution to journalArticleResearchpeer-review

138 Citations (Scopus)

Abstract

Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is coexpressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference-mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo.

Original languageEnglish
Pages (from-to)1199-1209
Number of pages11
JournalCancer Research
Volume72
Issue number5
DOIs
Publication statusPublished - 1 Mar 2012
Externally publishedYes

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