The lysosomal protease cysteine cathepsin B (CTSB) is a protease involved in carcinogenesis. In diverse types of neoplasia, CTSB has been reported to be overexpressed, mislocalized, and to have an increased abundance. Moreover, these increased expression and abundance has also been associated with worse prognosis and survival in several of these cancer entities. Previous studies, employing the MMTV-PyMT mouse model of breast cancer (PyMT), have shown that the differential expression of Ctsb can have an opposite impact on the tumor phenotype. The lack of Ctsb leads to a reduced tumor burden, whereas the transgenic overexpression results in an enhanced burden. Yet, the cancer secretome changes mediated by CTSB, contributing to this diverting tumor phenotype are not completely understood.
Cellular Repressor of E1A-stimulated Genes 1 (CREG1), a secreted/lysosomal glycoprotein, was detected -using mass-spectrometry proteomics methods- to be abundant in the cancer secretome of PyMT mice lacking Ctsb, whereas its abundance was reduced in the cancer secretome of PyMT mice with a transgenic overexpression of human CTSB. Interestingly, CREG1 has been reported to be able to impair cell proliferation and to promote cell differentiation; functions which could relate to the observed diverting tumor phenotype.
The measured changes in abundance of CREG1 -due to differential Ctsb expression- were corroborated and evidenced to be mediated by CTSB. Moreover, the addition of recombinant CREG1 to PyMT cancer cells led to reduced cell growth, migration, and invasion. In contrast, RNAi-mediated reduced expression of Creg1 in PyMT cells led to enhanced cell growth, migration, and invasion. Thus, the evidenced tumor suppressor-like functions of CREG1 might be key in the tumor-stroma interactions leading to the diverting tumor phenotype, observed in mice from the PyMT model with differential cathepsin B expression. Additionally, it further exemplifies how proteolysis at the tumor-stroma interface can influence the carcinogenic process.