title: A molecular analysis provides novel insights into androgen receptor signalling in breast cancer.
abstract: BACKGROUND
  Androgen 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.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  Taken 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.
authors.affiliation: National Institute of Pathology, ICMR, Safdarjang Hospital, New Delhi, India.
authors.forename: Jatin
authors.initials: J
authors.lastname: Mehta
authors.affiliation: National Institute of Pathology, ICMR, Safdarjang Hospital, New Delhi, India.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Department of Biochemistry, Central University of Rajasthan, Ajmer, India.
authors.forename: Chandi Charan
authors.initials: CC
authors.lastname: Mandal
authors.affiliation: National Institute of Pathology, ICMR, Safdarjang Hospital, New Delhi, India.
authors.forename: Sunita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone