HDAC inhibition does not induce estrogen receptor in human triple-negative breast cancer cell lines and patient-derived xenografts

• Published in: Breast cancer research and treatment Vol. 149; no. 1; pp. 81 - 89
• Main Authors: de Cremoux, Patricia, Dalvai, Mathieu, N’Doye, Olivia, Moutahir, Fatima, Rolland, Gaëlle, Chouchane-Mlik, Olfa, Assayag, Franck, Lehmann-Che, Jacqueline, Kraus-Berthie, Laurence, Nicolas, André, Lockhart, Brian Paul, Marangoni, Elisabetta, de Thé, Hugues, Depil, Stéphane, Bystricky, Kerstin, Decaudin, Didier
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.01.2015; Springer; Springer Nature B.V
• Subjects: Analysis; Benzofurans - administration & dosage; Breast cancer; Cancer research; Cancer therapies; Cell Proliferation - drug effects; Cyclin D1 - biosynthesis; Enzymes; Epidermal growth factor; Estrogen; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - genetics; Estrogen Receptor beta - antagonists & inhibitors; Estrogen Receptor beta - biosynthesis; Estrogens; Female; Gene Expression Regulation, Neoplastic - drug effects; Histone Deacetylase Inhibitors - administration & dosage; Histones - genetics; Hormones; Humans; Hydroxamic Acids - administration & dosage; Indoles - administration & dosage; Inhibitor drugs; Medicine; Medicine & Public Health; Oncology; Pathology; Phenols; Preclinical Study; Receptor, ErbB-2 - genetics; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Xenograft Model Antitumor Assays; HDAC inhibitor; Estrogen receptor; HER2; Xenografts; Triple-negative breast cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-014-3233-y

Several publications have suggested that histone deacetylase inhibitors (HDACis) could reverse the repression of estrogen receptor alpha (ERα) in triple-negative breast cancer (TNBC) cell lines, leading to the induction of a functional protein. Using different HDACis, vorinostat, panobinostat, and abexinostat, we therefore investigated this hypothesis in various human TNBC cell lines and patient-derived xenografts (PDXs). We used three human TNBC cell lines and three PDXs. We analyzed the in vitro toxicity of the compounds, their effects on the hormone receptors and hormone-related genes and protein expression both in vitro and in vivo models. We then explored intra-tumor histone H3 acetylation under abexinostat in xenograft models. Despite major cytotoxicity of all tested HDAC inhibitors and repression of deactylation-dependent CCND1 gene, neither ERα nor ERβ, ESR1 or ESR2 genes respectively, were re-expressed in vitro. In vivo, after administration of abexinostat for three consecutive days, we did not observe any induction of ESR1 or ESR1-related genes and ERα protein expression by RT-qPCR and immunohistochemical methods in PDXs. This observation was concomitant to the fact that in vivo administration of abexinostat increased intra-tumor histone H3 acetylation. These observations do not allow us to confirm previous studies which suggested that HDACis are able to convert ER-negative (ER−) tumors to ER-positive (ER+) tumors, and that a combination of HDAC inhibitors and hormone therapy could be proposed in the management of TNBC patients.