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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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2374-4677 |