Abstract
Estrogens play a pivotal role in breast cancer etiology, and endocrine therapy remains the main first line treatment for estrogen receptor‐alpha (ER α)‐positive breast cancer. ER are transcription factors whose activity is finely regulated by various regulatory complexes, including histone deacetylases (HDACs). Here, we investigated the role of HDAC 9 in ER α signaling and response to antiestrogens in breast cancer cells. Various Michigan Cancer Foundation‐7 (MCF 7) breast cancer cell lines that overexpress class II a HDAC 9 or that are resistant to the partial antiestrogen 4‐hydroxy‐tamoxifen (OHTam) were used to study phenotypic changes in response to ER ligands by using transcriptomic and gene set enrichment analyses. Kaplan–Meier survival analyses were performed using public transcriptomic datasets from human breast cancer biopsies. In MCF 7 breast cancer cells, HDAC 9 decreased ER α mRNA and protein expression and inhibited its transcriptional activity. Conversely, HDAC 9 mRNA was strongly overexpressed in OHT am‐resistant MCF 7 cells and in ER α‐negative breast tumor cell lines. Moreover, HDAC 9‐overexpressing cells were less sensitive to OHT am antiproliferative effects compared with parental MCF 7 cells. Several genes (including MUC 1, SMC 3 and S100P) were similarly deregulated in OHT am‐resistant and in HDAC 9‐overexpressing MCF 7 cells. Finally, HDAC 9 expression was positively associated with genes upregulated in endocrine therapy‐resistant breast cancers and high HDAC 9 levels were associated with worse prognosis in patients treated with OHT am. These results demonstrate the complex interactions of class II a HDAC 9 with ER α signaling in breast cancer cells and its effect on the response to hormone therapy