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 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.