Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection
Abstract Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-01878-8 |
| _version_ | 1827310440686813184 |
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| author | Tirza Bidany-Mizrahi Aya Shweiki Kian Maroun Lina Abu-Tair Bella Mali Rami I. Aqeilan |
| author_facet | Tirza Bidany-Mizrahi Aya Shweiki Kian Maroun Lina Abu-Tair Bella Mali Rami I. Aqeilan |
| author_sort | Tirza Bidany-Mizrahi |
| collection | DOAJ |
| description | Abstract Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC is essential. We previously showed that WW domain-containing oxidoreductase (WWOX) is commonly inactivated in TNBC and is implicated in the DNA damage response (DDR) through ATM and ATR activation. In this study, we investigated the interplay between WWOX and BRCA1, both frequently inactivated in TNBC, on mammary tumor development and on DNA double-strand break (DSB) repair choice. We generated and characterized a transgenic mouse model (K14-Cre;Brca1 fl/fl ;Wwox fl/fl ) and observed that mice lacking both WWOX and BRCA1 developed basal-like mammary tumors and exhibited a decrease in 53BP1 foci and an increase in RAD51 foci, suggesting impaired DSB repair. We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis. |
| first_indexed | 2024-04-24T19:59:51Z |
| format | Article |
| id | doaj.art-fde5a074f8b34b6c86d4bd817fca586a |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-24T19:59:51Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-fde5a074f8b34b6c86d4bd817fca586a2024-03-24T12:10:32ZengNature Publishing GroupCell Death Discovery2058-77162024-03-0110111110.1038/s41420-024-01878-8Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selectionTirza Bidany-Mizrahi0Aya Shweiki1Kian Maroun2Lina Abu-Tair3Bella Mali4Rami I. Aqeilan5The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of JerusalemThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of JerusalemThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of JerusalemThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of JerusalemDepartment of Pathology, Hadassah University HospitalThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of JerusalemAbstract Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC is essential. We previously showed that WW domain-containing oxidoreductase (WWOX) is commonly inactivated in TNBC and is implicated in the DNA damage response (DDR) through ATM and ATR activation. In this study, we investigated the interplay between WWOX and BRCA1, both frequently inactivated in TNBC, on mammary tumor development and on DNA double-strand break (DSB) repair choice. We generated and characterized a transgenic mouse model (K14-Cre;Brca1 fl/fl ;Wwox fl/fl ) and observed that mice lacking both WWOX and BRCA1 developed basal-like mammary tumors and exhibited a decrease in 53BP1 foci and an increase in RAD51 foci, suggesting impaired DSB repair. We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis.https://doi.org/10.1038/s41420-024-01878-8 |
| spellingShingle | Tirza Bidany-Mizrahi Aya Shweiki Kian Maroun Lina Abu-Tair Bella Mali Rami I. Aqeilan Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection Cell Death Discovery |
| title | Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection |
| title_full | Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection |
| title_fullStr | Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection |
| title_full_unstemmed | Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection |
| title_short | Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection |
| title_sort | unveiling the relationship between wwox and brca1 in mammary tumorigenicity and in dna repair pathway selection |
| url | https://doi.org/10.1038/s41420-024-01878-8 |
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