TonEBP regulates ESR1 transcription and ER-dependent proliferation in ER-positive breast cancer

Estrogen receptor α (ERα), encoded by ESR1 , is a central determinant of luminal breast cancer growth, yet the mechanisms sustaining basal ESR1 transcription remain incompletely defined. Here we identify tonicity-responsive enhancer-binding protein (TonEBP) as a promoter-associated regulator of ESR1 transcription and ER-dependent proliferation in ER-positive breast cancer. Elevated TonEBP expression correlated with adverse clinical outcomes across independent patient cohorts. In ER-positive cells, TonEBP depletion impaired proliferation, induced G1-phase accumulation, and attenuated ER signaling. A functional TonEBP-binding motif (TonE) was identified within the proximal ESR1 promoter; its mutation reduced promoter activity, and chromatin immunoprecipitation confirmed TonEBP enrichment at the endogenous locus. Consistently, TonEBP knockdown decreased ESR1 expression, ERα abundance, and estrogen response element–dependent transcription, while enhancing sensitivity to tamoxifen and doxorubicin. These findings support a model in which TonEBP sustains ERα expression through promoter-level regulation of ESR1 , linking stress-responsive transcriptional control to hormone-dependent growth in luminal breast cancer. • High TonEBP predicts poor outcomes in luminal breast cancer • TonEBP sustains ESR1 transcription and ERα expression • TonEBP drives ER-dependent proliferation in ER+ cells • TonEBP loss increases tamoxifen and doxorubicin sensitivity