ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness
Abstract Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05197-7 |
| _version_ | 1798004510850809856 |
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| author | Marcel Werner Anna Dyas Iwan Parfentev Geske E. Schmidt Iga K. Mieczkowska Lukas C. Müller-Kirschbaum Claudia Müller Stefan Kalkhof Oliver Reinhardt Henning Urlaub Frauke Alves Julia Gallwas Evangelos Prokakis Florian Wegwitz |
| author_facet | Marcel Werner Anna Dyas Iwan Parfentev Geske E. Schmidt Iga K. Mieczkowska Lukas C. Müller-Kirschbaum Claudia Müller Stefan Kalkhof Oliver Reinhardt Henning Urlaub Frauke Alves Julia Gallwas Evangelos Prokakis Florian Wegwitz |
| author_sort | Marcel Werner |
| collection | DOAJ |
| description | Abstract Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development. |
| first_indexed | 2024-04-11T12:24:53Z |
| format | Article |
| id | doaj.art-8323616185d34c74b6e02a3d92901d16 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T12:24:53Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8323616185d34c74b6e02a3d92901d162022-12-22T04:23:59ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911110.1038/s41419-022-05197-7ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressivenessMarcel Werner0Anna Dyas1Iwan Parfentev2Geske E. Schmidt3Iga K. Mieczkowska4Lukas C. Müller-Kirschbaum5Claudia Müller6Stefan Kalkhof7Oliver Reinhardt8Henning Urlaub9Frauke Alves10Julia Gallwas11Evangelos Prokakis12Florian Wegwitz13Department of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenBioanalytical Mass Spectrometry group, Max Planck Institute for Multidisciplinary SciencesDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and ImmunologyDepartment of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and ImmunologyTranslational Molecular Imaging, Max-Planck Institute for Multidisciplinary SciencesBioanalytical Mass Spectrometry group, Max Planck Institute for Multidisciplinary SciencesTranslational Molecular Imaging, Max-Planck Institute for Multidisciplinary SciencesDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenAbstract Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.https://doi.org/10.1038/s41419-022-05197-7 |
| spellingShingle | Marcel Werner Anna Dyas Iwan Parfentev Geske E. Schmidt Iga K. Mieczkowska Lukas C. Müller-Kirschbaum Claudia Müller Stefan Kalkhof Oliver Reinhardt Henning Urlaub Frauke Alves Julia Gallwas Evangelos Prokakis Florian Wegwitz ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness Cell Death and Disease |
| title | ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness |
| title_full | ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness |
| title_fullStr | ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness |
| title_full_unstemmed | ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness |
| title_short | ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness |
| title_sort | robo3s a novel robo3 short isoform promoting breast cancer aggressiveness |
| url | https://doi.org/10.1038/s41419-022-05197-7 |
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