Mutation of the androgen receptor causes oncogenic transformation of the prostate

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) signaling remains critical in prostate cancer, even with therapies targeting androgen levels.
• Mechanisms linking AR to prostate cancer progression, beyond mutation or amplification, require further investigation.

Purpose of the Study:

• To functionally investigate the direct role of altered androgen receptor (AR) function in spontaneous prostate cancer progression.
• To model specific AR alterations, including wild-type (AR-WT), promiscuous ligand response (AR-T857A), and altered function (AR-E231G), in transgenic mice.

Main Methods:

• Generated transgenic mouse models expressing distinct AR variants (AR-WT, AR-T857A, AR-E231G).
• Assessed the development and progression of prostate cancer in mice harboring these AR transgenes.
• Analyzed the impact of AR mutations on prostatic intraepithelial neoplasia, invasion, and metastasis.

Main Results:

• Transgenes for AR-WT and AR-T857A did not induce prostate cancer at comparable expression levels.
• Expression of AR-E231G, a mutation in the AR NH2-terminal domain affecting coregulator interactions, led to rapid prostatic intraepithelial neoplasia.
• AR-E231G expression resulted in invasive and metastatic prostate cancer in 100% of examined mice.

Conclusions:

• Demonstrates the oncogenic potential of steroid receptors, specifically the androgen receptor.
• Highlights altered AR function and coregulator interactions as critical drivers of prostate cancer initiation, invasion, and metastasis.
• Provides a novel mouse model for studying AR-driven prostate cancer progression.