Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation
Abstract Notch signaling is altered in breast cancer. Recent studies highlighted both tumor-suppressive and oncogenic roles for Notch in this tissue. The function of Jagged1, the most highly expressed Notch ligand in the mammary gland, is not well defined. Here we report that deletion of Jagged1 in...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-025-00545-6 |
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| author | Wen-Cheng Chung Wei Wang Lavanya Challagundla Charles D. Moore Sean E. Egan Keli Xu |
| author_facet | Wen-Cheng Chung Wei Wang Lavanya Challagundla Charles D. Moore Sean E. Egan Keli Xu |
| author_sort | Wen-Cheng Chung |
| collection | DOAJ |
| description | Abstract Notch signaling is altered in breast cancer. Recent studies highlighted both tumor-suppressive and oncogenic roles for Notch in this tissue. The function of Jagged1, the most highly expressed Notch ligand in the mammary gland, is not well defined. Here we report that deletion of Jagged1 in the mammary epithelium of virgin mice led to expansion of the mammary stem cell (MaSC) compartment and defective luminal differentiation associated with decreased expression of the progesterone receptor (PR). In contrast, deletion of Jagged1 in alveolar cells of pregnant mice had no effect on alveolar and lactogenic differentiation or post-lactational involution. Interestingly, deletion of Jagged1 promoted mouse mammary tumor formation from luminal cells but suppressed them from basal cells, associated with downregulation of Notch target genes Hey1 and Hey2, respectively. In agreement with mouse experiments, high expression of JAG1 and HEY1 are associated with better overall survival among patients with luminal tumors, whereas high expression of JAG1 and HEY2 are both associated with worse overall survival in basal subtype of human breast cancer. These results identified Jagged1 as an important regulator of mammary epithelial hierarchy and revealed differential roles of Jagged1-mediated Notch signaling in different subtypes of breast cancer arising from distinct cell types. |
| format | Article |
| id | doaj-art-a321b20800be41d2beca9bd780df0cbf |
| institution | Kabale University |
| issn | 2157-9024 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-a321b20800be41d2beca9bd780df0cbf2025-02-02T12:43:09ZengNature Publishing GroupOncogenesis2157-90242025-01-0114111010.1038/s41389-025-00545-6Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formationWen-Cheng Chung0Wei Wang1Lavanya Challagundla2Charles D. Moore3Sean E. Egan4Keli Xu5Department of Cell and Molecular Biology, University of Mississippi Medical CenterProgram in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick ChildrenDepartment of Cell and Molecular Biology, University of Mississippi Medical CenterDepartment of Cell and Molecular Biology, University of Mississippi Medical CenterProgram in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick ChildrenDepartment of Cell and Molecular Biology, University of Mississippi Medical CenterAbstract Notch signaling is altered in breast cancer. Recent studies highlighted both tumor-suppressive and oncogenic roles for Notch in this tissue. The function of Jagged1, the most highly expressed Notch ligand in the mammary gland, is not well defined. Here we report that deletion of Jagged1 in the mammary epithelium of virgin mice led to expansion of the mammary stem cell (MaSC) compartment and defective luminal differentiation associated with decreased expression of the progesterone receptor (PR). In contrast, deletion of Jagged1 in alveolar cells of pregnant mice had no effect on alveolar and lactogenic differentiation or post-lactational involution. Interestingly, deletion of Jagged1 promoted mouse mammary tumor formation from luminal cells but suppressed them from basal cells, associated with downregulation of Notch target genes Hey1 and Hey2, respectively. In agreement with mouse experiments, high expression of JAG1 and HEY1 are associated with better overall survival among patients with luminal tumors, whereas high expression of JAG1 and HEY2 are both associated with worse overall survival in basal subtype of human breast cancer. These results identified Jagged1 as an important regulator of mammary epithelial hierarchy and revealed differential roles of Jagged1-mediated Notch signaling in different subtypes of breast cancer arising from distinct cell types.https://doi.org/10.1038/s41389-025-00545-6 |
| spellingShingle | Wen-Cheng Chung Wei Wang Lavanya Challagundla Charles D. Moore Sean E. Egan Keli Xu Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation Oncogenesis |
| title | Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation |
| title_full | Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation |
| title_fullStr | Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation |
| title_full_unstemmed | Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation |
| title_short | Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation |
| title_sort | subtype specific role for jagged1 in promoting or inhibiting breast tumor formation |
| url | https://doi.org/10.1038/s41389-025-00545-6 |
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