Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer
Abstract Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockou...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-025-00787-y |
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| author | C. Toro S. Real S. Laurito M. T. Branham |
| author_facet | C. Toro S. Real S. Laurito M. T. Branham |
| author_sort | C. Toro |
| collection | DOAJ |
| description | Abstract Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer. |
| format | Article |
| id | doaj-art-c8fea32fc7bc45809ccb6ff8ef6c6a5f |
| institution | Kabale University |
| issn | 2374-4677 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj-art-c8fea32fc7bc45809ccb6ff8ef6c6a5f2025-08-20T03:43:20ZengNature Portfolionpj Breast Cancer2374-46772025-07-0111111210.1038/s41523-025-00787-yExploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancerC. Toro0S. Real1S. Laurito2M. T. Branham3Facultad de Ciencias Exactas y Naturales. Universidad Nacional de CuyoInstituto de Histología y Embriología de Mendoza (IHEM, Universidad Nacional de Cuyo, CONICET)Facultad de Ciencias Exactas y Naturales. Universidad Nacional de CuyoInstituto de Histología y Embriología de Mendoza (IHEM, Universidad Nacional de Cuyo, CONICET)Abstract Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer.https://doi.org/10.1038/s41523-025-00787-y |
| spellingShingle | C. Toro S. Real S. Laurito M. T. Branham Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer npj Breast Cancer |
| title | Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer |
| title_full | Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer |
| title_fullStr | Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer |
| title_full_unstemmed | Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer |
| title_short | Exploring ID4 as a driver of aggression and a therapeutic target in triple-negative breast cancer |
| title_sort | exploring id4 as a driver of aggression and a therapeutic target in triple negative breast cancer |
| url | https://doi.org/10.1038/s41523-025-00787-y |
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