title: Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors.
abstract: Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors. In this article, by using an "in silico" approach, we identified genomic functions that can be inhibited pharmacologically in basal-like tumors. Functional annotation analyses identified "cell division" and "regulation of transcription" as upregulated functions. When focus on cell division, we identified the polo-like kinase 1 (PLK) as an upregulated kinase. The PLK inhibitor Volasertib had the strongest anti-proliferative effect compared with other inhibitors against mitotic kinases. Gene expression analyses demonstrated that the BET inhibitor JQ1 reduced the expression of kinases involved in cell division, and synergized with Volasertib in a panel of triple negative cell lines. Combination of both agents augmented cell death. Similarly, combination of both compounds reduced the expression of stem cell markers. Globally, this data demonstrates the synergistic interaction between BET and PLK inhibitors, paving the way for their future clinical development.
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nieto-Jiménez
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Alcaraz-Sanabria
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: Verónica
authors.initials: V
authors.lastname: Corrales-Sánchez
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Serrano-Heras
authors.affiliation: Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Galán-Moya
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Serrano-Oviedo
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Burgos
authors.affiliation: Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Llopis
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocaña
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D000097869:Polo-Like Kinase 1; D000092468:Bromodomain Containing Proteins
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BET inhibitors; JQ1; breast cancer; polo-like kinases; triple negative breast cancer