Elevated GCN5 expression confers tamoxifen resistance by upregulating AIB1 expression in ER-positive breast cancer

Approximately 70% of breast cancers are estrogen receptor (ER)-positive and treated with endocrine therapy. A commonly used treatment agent, tamoxifen, shows high efficacy for improving prognosis. However, approximately one-third of patients treated with tamoxifen develop resistance to this drug. Here, we investigated the function of general control non-derepressible 5 (GCN5) and its downstream effectors in tamoxifen-resistant (TamR) breast cancer. TamR-MCF7 breast cancer cells maintained high GCN5 levels due to its attenuated proteasomal degradation. GCN5 overexpression upregulated amplified in breast cancer 1 (AIB1) expression, resulting in decreased p53 stability and tamoxifen resistance. Conversely, the sensitivity of GCN5-AIB1-overexpressing MCF7 cells to tamoxifen was restored by forced p53 expression. An in vivo study demonstrated a positive correlation between GCN5 and AIB1 and their contribution to tamoxifen resistance. We concluded that GCN5 promotes AIB1 expression and tamoxifen resistance in breast cancer by reducing p53 levels, suggesting the utility of GCN5 and its downstream effectors as therapeutic targets to either prevent or overcome tamoxifen resistance in breast cancer. •GCN5 and its downstream target, AIB1 is upregulated in tamoxifen-resistant breast cancer.•High level of GCN5 and AIB1 confers tamoxifen resistance via ubiquitination-mediated p53 degradation.•GCN5 silencing restored the sensitivity to tamoxifen treatment in vitro and in vivo.•GCN5 may potentially be a useful prognostic or predictive biomarker in tamoxifen treated patients.