期刊
ENDOCRINE-RELATED CANCER
卷 21, 期 4, 页码 T87-T103出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/ERC-13-0470
关键词
androgen receptor; splice variants; castration resistant prostate cancer; AR variants; metastasis; epithelial to mesenchymal transition
资金
- Veridex postdoctoral training grant
- National Cancer Institute [R01 CA127727]
- Robert B Goergen Prostate Cancer Foundation Young Investigator Award
- Department of Defense Physician Research Training Award [W81XWH-10-1-0483]
- National Institutes of Health [R01 CA174777]
- American Cancer Society Research Scholar Grant [RSG-12-031-01]
- Department of Defense Prostate Cancer Research Program New Investigator Award [W81XWH-10-1-0353]
- Masonic Cancer Center, University of Minnesota
As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor micro-environment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro-and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanismis the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.
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