Ben T Copeland1, Sumanta K Pal1, Eric C Bolton2, Jeremy O Jones1. 1. Department of Medical Oncology, City of Hope National Cancer Center, Duarte, California. 2. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
Abstract
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.
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 ARmalignancy shift. METHODS: In this review, we summarize the current knowledge of the ARmalignancy 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 ARmalignancy shift. Current evidence suggests that the ARmalignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. CONCLUSIONS: Reinterpretation of prostate cancer genomic classification systems in light of the ARmalignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the ARmalignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer.
Authors: Catherine C Elix; Meghan M Salgia; Maya Otto-Duessel; Ben T Copeland; Christopher Yoo; Michael Lee; Ben Yi Tew; David Ann; Sumanta K Pal; Jeremy O Jones Journal: Prostate Date: 2019-11-26 Impact factor: 4.104
Authors: Steven Kregel; Pia Bagamasbad; Shihan He; Elizabeth LaPensee; Yemi Raji; Michele Brogley; Arul Chinnaiyan; Marcin Cieslik; Diane M Robins Journal: Nucleic Acids Res Date: 2020-05-21 Impact factor: 16.971
Authors: Adam Sharp; Ilsa Coleman; Wei Yuan; Cynthia Sprenger; David Dolling; Daniel Nava Rodrigues; Joshua W Russo; Ines Figueiredo; Claudia Bertan; George Seed; Ruth Riisnaes; Takuma Uo; Antje Neeb; Jonathan Welti; Colm Morrissey; Suzanne Carreira; Jun Luo; Peter S Nelson; Steven P Balk; Lawrence D True; Johann S de Bono; Stephen R Plymate Journal: J Clin Invest Date: 2018-11-26 Impact factor: 14.808