title: Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression.
abstract: 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.
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Tholen
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Wolanski
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Stolze
authors.affiliation: Institute of Biochemistry and Molecular Biology, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg.
authors.forename: Marco
authors.initials: M
authors.lastname: Chiabudini
authors.affiliation: Institute of Pathology, Friedrich-Schiller University, 07743 Jena, Germany.
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Gajda
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg; Comprehensive Cancer Center/German Cancer Consortium (DKTK), 79106 Freiburg.
authors.forename: Peter
authors.initials: P
authors.lastname: Bronsert
authors.affiliation: Comprehensive Cancer Center/German Cancer Consortium (DKTK), 79106 Freiburg; Clinic for Gynecology, University Medical Center Freiburg, 79106 Freiburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Stickeler
authors.affiliation: Institute of Biochemistry and Molecular Biology, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rospert
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg; Comprehensive Cancer Center/German Cancer Consortium (DKTK), 79106 Freiburg. Electronic address: thomas.reinheckel@uniklinik-freiburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056668:Cathepsin L / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D014176:Protein Biosynthesis; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D020121:5' Untranslated Regions; D012334:RNA, Neoplasm; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse
keywords: alternative splicing; breast cancer; cysteine protease; metastasis; translation control