Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer

Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Cancer Research (Impact Factor: 9.33). 03/2012; 72(5):1199-209. DOI: 10.1158/0008-5472.CAN-11-2759
Source: PubMed


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.

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Available from: Laura E Edgington-Mitchell, Mar 02, 2014
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    • "On the other hand, AGR2 gene overexpression significantly increased CTSB and CTSD expression [35]. CTSB and CTSD contribute to tumor cell invasion and angiogenesis and are commonly associated with metastasis [38], [46], [48], [52]. Cathepsin is known to remodel the surrounding ECM by proteolysis, allowing tumor cell invasion and metastasis [66]. "
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    • "Cell 154, 1–14, July 18, 2013 ª2013 Elsevier Inc. 9 Please cite this article in press as: Song et al., MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family- Dependent Chromatin Remodeling, Cell (2013), Interestingly, in this analysis miR-22 was also found to be significantly coexpressed with genes involved in breast cancer metastasis, including those that encode matrix metalloproteases 11 and 1 (Pearson r = 0.536 and 0.392, respectively), cathepsin B (0.500), integrin a11 (0.425), TGF-bR-associated protein (0.416), collagen Xa1 (0.411), TGF-b1 (0.407), fibronectin 1 (0.403), and laminin a5 (0.399) (Bierie and Moses, 2006; McCarthy et al., 1985; Melisi et al., 2008; Radisky and Radisky, 2010; Vuoristo et al., 2007; Withana et al., 2012) (Table S1). This observation also supports the notion that in breast cancer miR-22 is prometastatic and contributes to aggressive disease. "
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    • "Balicatib inhibits cathepsin K and showed potential to inhibit osteolysis and regain bone mass, but it was withdrawn from clinical trials due to safety issues [73] ; Odanacatib, another cathepsin K inhibitor, was also withdrawn from clinical trials for breast cancer bone metastasis for safety concerns [11] [74] . Most recently, intraperitoneal injections of the cathepsin B inhibitor CA-074 into mice in the 4T1.2 model (a breast cancer model that exhibits spontaneous bone metastases) reduced bone metastases significantly (P < 0.05), indicating an important role for cathepsin B in late-stage skeletal metastasis [75] . "
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