Oncotarget

Research Papers:

Bromodomain inhibition shows antitumoral activity in mice and human luminal breast cancer

Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Pere Llinàs-Arias, Laura Roa, Fernando Setien, Marta Soler, Manuel Castro de Moura, James E. Bradner, Eva Gonzalez-Suarez, Catia Moutinho _ and Manel Esteller

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Oncotarget. 2017; 8:51621-51629. https://doi.org/10.18632/oncotarget.18255

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Abstract

Montserrat Pérez-Salvia1, Laia Simó-Riudalbas1, Pere Llinàs-Arias1, Laura Roa1, Fernando Setien1, Marta Soler1, Manuel Castro de Moura1, James E. Bradner2, Eva Gonzalez-Suarez1, Catia Moutinho1 and Manel Esteller1,3,4

1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

2Novartis Institutes for Biomedical Research, Cambridge, MA, USA

3Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain

4Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

Correspondence to:

Catia Moutinho, email: cmoutinho@idibell.cat

Manel Esteller, email: mesteller@idibell.cat

Keywords: luminal breast cancer, bromodomain inhibitor, C-MYC, JQ1, mice model

Received: February 28, 2017     Accepted: May 04, 2017     Published: May 29, 2017

ABSTRACT

BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1). We have also applied these in vitro findings in an in vivo model by studying a transgenic mouse model representing the luminal B subtype of breast cancer, the MMTV-PyMT, in which the mouse mammary tumor virus promoter is used to drive the expression of the polyoma virus middle T-antigen to the mammary gland. We have observed that the use of the BET bromodomain inhibitor for the treatment of established breast neoplasms developed in the MMTV-PyMT model shows antitumor potential. Most importantly, if JQ1 is given before the expected time of tumor detection in the MMTV-PyMT mice, it retards the onset of the disease and increases the survival of these animals. Thus, our findings indicate that the use of bromodomain inhibitors is of great potential in the treatment of luminal breast cancer and merits further investigation.


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