Abstract
Previous clinical and experimental evidence strongly supports a breast cancer-promoting function of the lysosomal protease cathepsin B. However, the cathepsin B-dependent molecular pathways are not completely understood. Here, we studied the cathepsin-mediated secretome changes in the context of the MMTV-PyMT breast cancer mouse model. Employing the cell-conditioned media from tumor-macrophage co-cultures, as well as tumor interstitial fluid obtained by a novel strategy from PyMT mice with differential cathepsin B expression, we identified an important proteolytic and lysosomal signature, highlighting the importance of this organelle and these enzymes in the tumor micro-environment. The Cellular Repressor of E1A Stimulated Genes 1 (CREG1), a secreted endolysosomal glycoprotein, displayed reduced abundance upon over-expression of cathepsin B as well as increased abundance upon cathepsin B deletion or inhibition. Moreover, it was cleaved by cathepsin B in vitro. CREG1 reportedly could act as tumor suppressor. We show that treatment of PyMT tumor cells with recombinant CREG1 reduced proliferation, migration, and invasion; whereas, the opposite was observed with reduced CREG1 expression. This was further validated in vivo by orthotopic transplantation. Our study highlights CREG1 as a key player in tumor–stroma interaction and suggests that cathepsin B sustains malignant cell behavior by reducing the levels of the growth suppressor CREG1 in the tumor microenvironment.
Highlights
Many proteolytic enzymes are mechanistically linked to the progression and metastasis of carcinomas [1]
As the results suggest a posttranscriptional regulation of Cellular Repressor of E1A Stimulated Genes 1” (CREG1) by the cathepsins, we determined whether CREG1 would be a direct substrate for cathepsin B (CTSB) and/or cathepsin Z (CTSZ)
In the MMTV-PyMT model of metastasizing breast cancer, the transgenic expression of human CTSB is associated with faster tumor growth, enlarged tumor size, increased number and size of metastasis, and higher grade of malignancy [16, 19]
Summary
Many proteolytic enzymes are mechanistically linked to the progression and metastasis of carcinomas [1]. Cancer cells are thought to be able to invade the tumor stroma more This idea does not provide a stringent explanation of the frequently observed anti-proliferative effects of cathepsin inhibition on cancer cell proliferation [2, 13]. This means that the genuine functions of active cathepsins must be either the activation of growth-promoting substrates or the inactivation of growth-suppressive proteins. The latter might be more likely to occur, because there are relatively few examples for selective activating cleavages by cathepsins, especially outside the secretory cell compartment [12]
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