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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
A molecular analysis provides novel insights into androgen receptor signalling in breast cancer
Jatin Mehta1, Shailendra Asthana1, Chandi Charan Mandal2
1National Institute of Pathology, ICMR, Safdarjang Hospital, New Delhi, India.
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.
Methods/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.
Conclusion:
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.
Insights
Androgen Receptor (AR) signaling drives breast cancer progression by upregulating cell cycle genes and downregulating apoptosis genes. Bicalutamide treatment reverses these effects, suggesting its potential use in therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen Receptor (AR) is a key transcription factor in development and carcinogenesis.
- AR plays a role in breast and prostate cancer progression.
- Understanding AR regulatory mechanisms in ER-/AR+ breast cancer is crucial for novel therapeutic targets.
Purpose of the Study:
- To identify and validate Androgen Receptor (AR) targets in ER-/AR+ breast cancer.
- To elucidate the mechanistic details of AR's function in breast cancer progression.
- To explore novel therapeutic strategies for AR-positive breast cancers.
Main Methods:
- Bioinformatic analysis to identify AR targets.
- RT-qPCR and ChIP assays to validate gene regulation by 5α-dihydrotestosterone (DHT) in MDA-MB-453 cells.
- Rigid-body docking and electrostatic calculations to determine AR DNA-binding domain interactions.
Main Results:
- Identified 75 AR targets involved in cell cycle, apoptosis, and metabolism.
- DHT upregulates cell cycle genes (except MAD1L1) and downregulates apoptosis genes.
- DHT promotes proliferation and decreases apoptosis; bicalutamide reverses these effects.
- Novel AR residues (K567, K588, K591, R592) identified in DNA binding.
Conclusions:
- AR signaling promotes breast cancer progression via modulation of cell cycle and apoptosis.
- Bicalutamide effectively reverses DHT-induced effects in breast cancer cells.
- Proposes bicalutamide combined with taxanes as a novel therapy for AR-signaling positive TNBCs.
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