The androgen receptor malignancy shift in prostate cancer

BT Copeland, SK Pal, EC Bolton, JO Jones - The Prostate, 2018 - Wiley Online Library
BT Copeland, SK Pal, EC Bolton, JO Jones
The Prostate, 2018Wiley Online Library
Background Androgens and the androgen receptor (AR) are necessary for the development,
function, and homeostatic growth regulation of the prostate gland. However, once prostate
cells are transformed, the AR is necessary for the proliferation and survival of the malignant
cells. This change in AR function appears to occur in nearly every prostate cancer. We have
termed this the AR malignancy shift. Methods In this review, we summarize the current
knowledge of the AR malignancy shift, including the DNA‐binding patterns that define the …
Background
Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift.
Methods
In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA‐binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications.
Results
In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells.
Conclusions
Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer.
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