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

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

doi:10.18632/oncotarget.18255

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.

Highlights

Breast cancer is a leading cause of cancer death in women, estimated to account for more than 450,000 deaths worldwide every year [1]
Classical clinical and pathological markers, such as the status of the estrogen and progesterone receptors and human epidermal growth factor 2 (HER2) gene amplification, are useful for classifying patients according to prognosis and adequate treatments, but it has been the emergence of genomic technologies, such as global expression profiling, that has allowed an intrinsic molecular classification www.impactjournals.com/oncotarget
We have analyzed the effect of the BET bromodomain inhibitor JQ1 in the context of luminal breast cancer in mouse models and human cells

Summary

Introduction

Breast cancer is a leading cause of cancer death in women, estimated to account for more than 450,000 deaths worldwide every year [1]. Classical clinical and pathological markers, such as the status of the estrogen and progesterone receptors and human epidermal growth factor 2 (HER2) gene amplification, are useful for classifying patients according to prognosis and adequate treatments, but it has been the emergence of genomic technologies, such as global expression profiling, that has allowed an intrinsic molecular classification www.impactjournals.com/oncotarget [2,3,4] In this regard, five distinct intrinsic molecular subtypes are recognized: luminal A, luminal B, HER2 enriched, basal-like and claudin-low, together with a normal breast-like group [2,3,4]. Given the high frequency of luminal breast cancer, the generation of endocrine therapy-associated resistances and the poor outcome of the luminal B subtype, the development of new drugs for these patients is essential

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