title: In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment.
abstract: Triple-negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy, and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain-containing proteins affecting the expression of transcription factors, therefore modifying the expression of relevant oncogenic genes. In the present article, by using an in silico approach, we have identified the expression of upregulated transcription factors in TNBC compared with normal breast. Treatment with JQ1, a well-characterized BET inhibitor, modified some transcription factors, including DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). In cell line models, administration of JQ1 or OTX015, another BET inhibitor, produced a significant antiproliferative effect and synergized with chemotherapies. Biochemical evaluation demonstrated an arrest at G1 as the main mechanism of action with a clear increase of p27. Addition of these compounds to chemotherapy induced apoptosis compared to each agent given alone. Evaluation of JQ1 in xenografted tumors in nude mice showed a profound antitumoral effect with a reduction of DEPDC, FOXM1, and LM04, in addition to an increase of p27. Globally, our data demonstrate the antitumor effect of this new family of compounds in TNBC, paving the way for its future clinical development. Mol Cancer Ther; 15(8); 1823-33. ©2016 AACR.
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez-Peña
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Serrano-Heras
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Corrales-Sánchez
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain. albertoo@sescam.jccm.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocaña
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods; D066264:Datasets as Topic; D004195:Disease Models, Animal; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D014157:Transcription Factors; D014230:Triazoles