NDLI: A molecular analysis provides novel insights into androgen receptor signalling in breast cancer.

Content Provider	Directory of Open Access Journals (DOAJ)
Author	Jatin Mehta Shailendra Asthana Chandi Charan Mandal Sunita Saxena
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.
e-ISSN	19326203
DOI	10.1371/journal.pone.0120622
Journal	PLoS ONE
Issue Number	3
Volume Number	10
Language	English
Publisher	Public Library of Science (PLoS)
Publisher Date	2015-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Medicine Science
Content Type	Text
Resource Type	Article

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