GATA3 and YBX1 are associated with ER-specific metabolic programs and vulnerabilities in breast cancer

Estrogen receptor (ER) status is a key clinical classifier in breast cancer, but its relationship with tumor metabolism remains incompletely understood. We integrated transcriptomic data from 1992 tumors with metabolomic, single-cell, and functional analyses to define ER-associated metabolic programs. ER-positive (ER+ve) tumors exhibited transcriptomic signatures of oxidative metabolism, including fatty acid and branched-chain amino acid catabolism, whereas ER-negative (ER-ve) tumors showed glycolytic and lipogenic reprogramming. Network analysis identified GATA3 and YBX1 as major context-specific regulators associated with ER+ve and ER-ve metabolic states, respectively. Single-cell analyses supported these findings, demonstrating enrichment of GATA3 in ER+ve tumor cells and YBX1 activity in triple-negative breast cancer cells. Functional perturbation and 13C-tracer experiments showed that altering GATA3 or YBX1 expression changed glucose and lipid substrate utilization. Loss of GATA3 increased ER+ve cell sensitivity to glycolytic and lipogenic inhibitors, doxorubicin, and combination treatments. In contrast, YBX1 depletion reduced sensitivity to metabolic inhibitors but enhanced doxorubicin sensitivity in ER-ve cells. Clinically, GATA3 regulon activity was independently associated with prognosis in ER+ve disease, whereas YBX1 regulon activity lacked independent prognostic significance after adjustment for clinical variables. These findings identify GATA3 and YBX1 as ER-specific metabolic regulators linking transcriptional programs, metabolic states, and therapeutic response in breast cancer. Integrative transcriptomic, single-cell and functional analyses identify GATA3 and YBX1 as estrogen receptor-specific regulators linking metabolic reprogramming to therapeutic vulnerability in breast cancer.