2012 Current Cancer Dedicated to bringing the latest news and information on cancer diagnosis, treatment and prevention.

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice.

Sevenich L, Schurigt U, Sachse K, Gajda M, Werner F, Müller S, Vasiljeva O, Schwinde A, Klemm N, Deussing J, Peters C, Reinheckel T.

Institute of Molecular Medicine and Cell Research Faculty of Biology, Albert Ludwigs University, Freiburg D-79104 Institute of Pathology, Friedrich Schiller University, Jena D-07740, Germany Spemann Graduate School of Biology and Medicine Ludwig Heilmeyer Comprehensive Cancer Center and Center for Biological Signaling Studies, Albert Ludwigs University, Freiburg D-79106, Germany.

The lysosomal cysteine proteases cathepsin B (Ctsb) and cathepsin Z (Ctsz, also called cathepsin X/P) have been implicated in cancer pathogenesis. Compensation of Ctsb by Ctsz in Ctsb (-/-) mice has been suggested. To further define the functional interplay of these proteases in the context of cancer, we generated Ctsz null mice, crossed them with Ctsb-deficient mice harboring a transgene for the mammary duct-specific expression of polyoma middle T oncogene (PymT), and analyzed the effects of single and combined Ctsb and Ctsz deficiencies on breast cancer progression. Single Ctsb deficiency resulted in delayed detection of first tumors and reduced tumor burden, whereas Ctsz-deficient mice had only a prolonged tumor-free period. However, only a trend toward reduced metastatic burden without statistical significance was detected in both single mutants. Strikingly, combined loss of Ctsb and Ctsz led to additive effects, resulting in significant and prominent delay of early and advanced tumor development, improved histopathologic tumor grading, as well as a 70% reduction in the number of lung metastases and an 80% reduction in the size of these metastases. We conclude that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.