title: HDAC inhibition does not induce estrogen receptor in human triple-negative breast cancer cell lines and patient-derived xenografts.
abstract: 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.
authors.affiliation: APHP Hôpital Saint-Louis, Molecular Oncoloy Unit and University Paris-Diderot, PRES Paris Cité, INSERM/CNRS UMR944/7212, 1, Avenue Claude Vellefaux, 75010, Paris, France, patricia.de-cremoux@sls.aphp.fr.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Cremoux
authors.forename: Mathieu
authors.initials: M
authors.lastname: Dalvai
authors.forename: Olivia
authors.initials: O
authors.lastname: N'Doye
authors.forename: Fatima
authors.initials: F
authors.lastname: Moutahir
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Rolland
authors.forename: Olfa
authors.initials: O
authors.lastname: Chouchane-Mlik
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lehmann-Che
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthie
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.forename: Brian Paul
authors.initials: BP
authors.lastname: Lockhart
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bystricky
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
mesh_terms: D001572:Benzofurans / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006657:Histones / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D000077767:Panobinostat; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D001572:Benzofurans; D019938:Cyclin D1; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077337:Vorinostat; C530104:CCND1 protein, human; C506487:ESR1 protein, human; C508053:ERBB2 protein, human; C512352:abexinostat