Abstract
BackgroundAndrogen Receptor (AR) is an essential transcription factor for the development of secondary sex characteristics, spermatogenesis and carcinogenesis. Recently AR has been implicated in the development and progression of breast and prostate cancers. Although some of the functions of the AR are known but the mechanistic details of these divergent processes are still not clear. Therefore understanding the regulatory mechanisms of the functioning of the AR in ER-/AR+ breast cancer will provide many novel targets for the purpose of therapeutic intervention.Methods/ResultsUsing bioinformatics tools, we have identified 75 AR targets having prominent roles in cell cycle, apoptosis and metabolism. Herein, we validated 10 genes as AR targets by studying the regulation of these genes in MDA-MB-453 cell line on stimulation by androgens like 5α-dihydrotestosterone (DHT), using RT-qPCR and ChIP assay. It was observed that all the identified genes involved in cell cycle except MAD1L1 were found to be up regulated whereas expression of apoptosis related genes was decreased in response to DHT treatment. We performed an exhaustive, rigid-body docking between individual ARE and DNA binding domain (DBD) of the AR protein and it was found that novel residues K567, K588, K591 and R592 are involved in the process of DNA binding. To verify these specific DNA-protein interactions electrostatic energy term calculations for each residue was determined using the linearized Poisson–Boltzmann equation. Our experimental data showed that treatment of breast cancer cells with DHT promotes cell proliferation and decreases apoptosis. It was observed that bicalutamide treatment was able to reverse the effect of DHT.ConclusionTaken together, our results provide new insights into the mechanism by which AR promotes breast cancer progression. Moreover our work proposes to use bicalutamide along with taxanes as novel therapy for the treatment of TNBCs, which are positive for downstream AR signalling.
Highlights
Androgen receptor (AR) belongs to a family of intracellular steroid hormone receptors that function as ligand dependent transcription factor which regulates target gene expression
Our results provide new insights into the mechanism by which AR promotes breast cancer progression
Our work proposes to use bicalutamide along with taxanes as novel therapy for the treatment of triple negative breast cancers (TNBCs), which are positive for downstream AR signalling
Summary
Androgen receptor (AR) belongs to a family of intracellular steroid hormone receptors that function as ligand dependent transcription factor which regulates target gene expression. AR is responsible for mediating a myriad of physiological function of the androgens like male sexual development, spermatogenesis, maintaining bone mineral density, stimulating erythropoiesis, production of prostate-specific proteins and it regulates several aspects of cell metabolism like lipid biosynthesis [1,2,3]. Exposed NLS aids in the translocation of AR to the nucleus, where it binds to androgen-response elements (AREs) present in the promoters of several target genes in a tissue-specific manner. AR recruits many other proteins, such as general transcription factors and RNA polymerase to the activate androgen-responsive genes [4]. Understanding the regulatory mechanisms of the functioning of the AR in ER-/AR+ breast cancer will provide many novel targets for the purpose of therapeutic intervention.
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