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.

中文翻译：

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侵袭性细胞生长的抑制因子CREG1受组织蛋白酶的负调控。

以前的临床和实验证据强烈支持溶酶体蛋白酶组织蛋白酶B的促进乳腺癌的功能。但是，组织蛋白酶B依赖的分子途径尚不完全清楚。在这里，我们研究了组织蛋白酶介导的分泌组在MMTV-PyMT乳腺癌小鼠模型中的变化。利用来自肿瘤-巨噬细胞共培养物的细胞条件培养基，以及通过新策略从具有不同组织蛋白酶B表达的PyMT小鼠获得的肿瘤间质液，我们确定了重要的蛋白水解和溶酶体标记，突出了该细胞器和这些酶在肿瘤的微环境中。E1A刺激的基因1（CREG1），一种分泌的溶酶体糖蛋白的细胞阻遏物，当组织蛋白酶B过度表达时，显示出降低的丰度，以及在组织蛋白酶B缺失或抑制时显示出的丰度增加。此外，它在体外被组织蛋白酶B切割。据报道，CREG1可以充当肿瘤抑制因子。我们显示，用重组CREG1治疗PyMT肿瘤细胞可减少增殖，迁移和侵袭。相反，观察到相反的情况，CREG1表达降低。通过原位移植在体内进一步证实了这一点。我们的研究突出了CREG1在肿瘤-基质相互作用中的关键作用，并建议组织蛋白酶B通过降低肿瘤微环境中生长抑制因子CREG1的水平来维持恶性细胞行为。据报道，CREG1可以充当肿瘤抑制因子。我们显示，用重组CREG1治疗PyMT肿瘤细胞可减少增殖，迁移和侵袭。相反，观察到相反的情况，CREG1表达降低。通过原位移植在体内进一步证实了这一点。我们的研究突出了CREG1在肿瘤-基质相互作用中的关键作用，并建议组织蛋白酶B通过降低肿瘤微环境中生长抑制因子CREG1的水平来维持恶性细胞行为。据报道，CREG1可以充当肿瘤抑制因子。我们显示，用重组CREG1治疗PyMT肿瘤细胞可减少增殖，迁移和侵袭。相反，观察到相反的情况，CREG1表达降低。通过原位移植在体内进一步证实了这一点。我们的研究突出了CREG1在肿瘤-基质相互作用中的关键作用，并建议组织蛋白酶B通过降低肿瘤微环境中生长抑制因子CREG1的水平来维持恶性细胞行为。