title: Cathepsin B inhibition limits bone metastasis in breast cancer.
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.
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Nimali P
authors.initials: NP
authors.lastname: Withana
authors.forename: Galia
authors.initials: G
authors.lastname: Blum
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Sameni
authors.forename: Clare
authors.initials: C
authors.lastname: Slaney
authors.forename: Arulselvi
authors.initials: A
authors.lastname: Anbalagan
authors.forename: Mary B
authors.initials: MB
authors.lastname: Olive
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Bidwell
authors.forename: Laura
authors.initials: L
authors.lastname: Edgington
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Kamiar
authors.initials: K
authors.lastname: Moin
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bogyo
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Parker
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000502:physiology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D004151:Dipeptides; C404948:JPM 565; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B; D007930:Leucine