Title |
Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer
|
---|---|
Published in |
Cancer Research, March 2012
|
DOI | 10.1158/0008-5472.can-11-2759 |
Pubmed ID | |
Authors |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 40% |
Tunisia | 1 | 20% |
Unknown | 2 | 40% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United Kingdom | 1 | <1% |
United States | 1 | <1% |
Australia | 1 | <1% |
Unknown | 155 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 37 | 23% |
Researcher | 25 | 16% |
Student > Master | 23 | 15% |
Student > Doctoral Student | 11 | 7% |
Student > Bachelor | 11 | 7% |
Other | 20 | 13% |
Unknown | 31 | 20% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 37 | 23% |
Agricultural and Biological Sciences | 36 | 23% |
Chemistry | 13 | 8% |
Medicine and Dentistry | 12 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 7 | 4% |
Other | 15 | 9% |
Unknown | 38 | 24% |