Research Papers:

Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors

Cristina Nieto-Jiménez _, Ana Alcaraz-Sanabria, Javier Pérez-Peña, Verónica Corrales-Sánchez, Gemma Serrano-Heras, Eva M. Galán-Moya, Leticia Serrano-Oviedo, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Atanasio Pandiella and Alberto Ocaña

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Oncotarget. 2017; 8:19478-19490. https://doi.org/10.18632/oncotarget.14465

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Cristina Nieto-Jiménez1, Ana Alcaraz-Sanabria1, Javier Pérez-Peña1, Verónica Corrales-Sánchez1, Gemma Serrano-Heras1, Eva M. Galán-Moya3, Leticia Serrano-Oviedo1, Juan Carlos Montero2, Miguel Burgos3, Juan Llopis3, Atanasio Pandiella2, Alberto Ocaña3

1Translational Research Unit, Albacete University Hospital, Albacete, Spain

2Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain

3Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain

Correspondence to:

Alberto Ocaña, email: [email protected]

Keywords: breast cancer, triple negative breast cancer, polo-like kinases, BET inhibitors, JQ1

Received: June 20, 2016    Accepted: November 07, 2016    Published: January 3, 2017


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.

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