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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.

SUBMITTER: Withana NP

PROVIDER: S-EPMC3538126 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Cathepsin B inhibition limits bone metastasis in breast cancer.

Withana Nimali P NP Blum Galia G Sameni Mansoureh M Slaney Clare C Anbalagan Arulselvi A Olive Mary B MB Bidwell Bradley N BN Edgington Laura L Wang Ling L Moin Kamiar K Sloane Bonnie F BF Anderson Robin L RL Bogyo Matthew S MS Parker Belinda S BS

Cancer research 20120119 5

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 therapeuti ...[more]

PMID: 22266111

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Dataset Information

Cathepsin B inhibition limits bone metastasis in breast cancer.

Publications

Cathepsin B inhibition limits bone metastasis in breast cancer.

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