Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression*

Background: Translational regulation might underlie the high expression levels of the protease cathepsin L (CTSL) associated with poor breast cancer prognosis. Results: Translation of CTSL mRNA is highly stress-resistant and promotes metastasis of murine breast cancer. Conclusion: CTSL mRNA circumvents translational shutdown in cancer-associated stress conditions. Significance: High expression of a metastasis promoting protease is maintained by translational regulation. The cysteine protease cathepsin L (CTSL) is often thought to act as a tumor promoter by enhancing tumor progression and metastasis. This goes along with increased CTSL activity in various tumor entities; however, the mechanisms leading to high CTSL levels are incompletely understood. With the help of the polyoma middle T oncogene driven breast cancer mouse model expressing a human CTSL genomic transgene, we show that CTSL indeed promotes breast cancer metastasis to the lung. During tumor formation and progression high expression levels of CTSL are maintained by enduring translation of CTSL mRNA. Interestingly, human breast cancer specimens expressed the same pattern of 5′ untranslated region (UTR) splice variants as the transgenic mice and the human cancer cell line MDA-MB 321. By polyribosome profiling of tumor tissues and human breast cancer cells, we observe an intrinsic resistance of CTSL to stress-induced shutdown of translation. This ability can be attributed to all 5′ UTR variants of CTSL and is not dependent on a previously described internal ribosomal entry site motif. In conclusion, we provide in vivo functional evidence for overexpressed CTSL as a promoter of lung metastasis, whereas high CTSL levels are maintained during tumor progression due to stress-resistant mRNA translation.

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