Increased expression of the HDAC9 gene is associated with antiestrogen resistance of breast cancers

• Published in: Molecular oncology 2019-07, Vol.13 (7), p.1534-1547
• Main Authors: Linares, Aurélien, Assou, Said, Lapierre, Marion, Thouennon, Erwan, Duraffourd, Céline, Fromaget, Carole, Boulahtouf, Abdelhay, Tian, Gao, Ji, Jiafu, Sahin, Ozgur, Badia, Eric, Boulle, Nathalie, Cavaillès, Vincent
• Format: Article
• Language: English
• Subjects: Analysis; antiestrogen resistance; Antiestrogens; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Hormonal - pharmacology; Biopsy; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer; Cell growth; cell proliferation; Datasets; Development and progression; DNA binding proteins; DNA methylation; Drug Resistance, Neoplasm; Endocrine therapy; Epigenetics; Estrogen; Estrogen Antagonists - pharmacology; estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; Etiology; Female; Gene expression; Genes; Genetic aspects; Genetic engineering; Health aspects; histone deacetylase; Histone Deacetylases - genetics; Histones; Humans; Ligands; MCF-7 Cells; Plasmids; Proteins; Repressor Proteins - genetics; RNA; Transcription factors; Transcriptome - drug effects; Transcriptomics; Tumor cell lines; Tumors; Up-Regulation - drug effects
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12505

Estrogens play a pivotal role in breast cancer etiology, and endocrine therapy remains the main first line treatment for estrogen receptor‐alpha (ERα)‐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 HDAC9 in ERα signaling and response to antiestrogens in breast cancer cells. Various Michigan Cancer Foundation‐7 (MCF7) breast cancer cell lines that overexpress class IIa HDAC9 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 MCF7 breast cancer cells, HDAC9 decreased ERα mRNA and protein expression and inhibited its transcriptional activity. Conversely, HDAC9 mRNA was strongly overexpressed in OHTam‐resistant MCF7 cells and in ERα‐negative breast tumor cell lines. Moreover, HDAC9‐overexpressing cells were less sensitive to OHTam antiproliferative effects compared with parental MCF7 cells. Several genes (including MUC1, SMC3 and S100P) were similarly deregulated in OHTam‐resistant and in HDAC9‐overexpressing MCF7 cells. Finally, HDAC9 expression was positively associated with genes upregulated in endocrine therapy‐resistant breast cancers and high HDAC9 levels were associated with worse prognosis in patients treated with OHTam. These results demonstrate the complex interactions of class IIa HDAC9 with ERα signaling in breast cancer cells and its effect on the response to hormone therapy. Antiestrogens are commonly used to treat breast cancers which express estrogen receptors, but tumors usually become resistant to such hormonal manipulation. This study demonstrates that in breast cancer cells, histone deacetylase 9 (HDAC9) strongly interacts with estrogen signaling and plays a role in antiestrogen resistance. HDAC9 might represent a new predictive marker and a novel therapeutic target for endocrine‐resistant breast cancers.