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.