Context-Dependent Interaction of the Androgen Receptor with Oncogenic Pathways Common to Prostate Cancer.

androgen receptor;prostate cancer;ETV1;PTEN;Genetics;Health Sciences;Science;Human Genetics

Higgins, Jacob EmersonLi, Jun ;

University of Michigan

关键词: androgen receptor;    prostate cancer;    ETV1;    PTEN;    Genetics;    Health Sciences;    Science;    Human Genetics;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/113291/jakemon_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Androgen receptor (AR) is a hormone-responsive transcription factor central to prostate cancer (PCa) onset and progression. Therapies targeting AR signaling are initially successful, yet acquired resistance is a major problem. This thesis examines how AR cooperates with common pathways of oncogene activation and tumor suppressor loss in PCa.Recurrent genomic rearrangements in PCa fuse the coding region of ETS family transcription factors with androgen-responsive regulatory elements, driving high expression in half of all tumors. Oncogenic ETS proteins promote early neoplasia and invasion in model systems, yet their prognostic value is unclear. Loss of the tumor suppressor PTEN occurs frequently in PCa, is associated with poor prognosis and treatment resistance, and causes neoplasia in model systems.To probe the interaction of the androgen axis with oncogenic ETS expression and PTEN loss, mice expressing a stronger or weaker humanized AR allele were crossed with mice overexpressing the less-studied ETS factor ETV1 or lacking one Pten allele. While AR strength did not affect ETV1-driven neoplasia, global gene expression analysis by RNA-seq revealed that ETV1 strongly antagonized AR transcriptional activity. Repressed targets included tumor suppressors and prostate differentiation genes such as Nkx3-1 and Hoxb13. This suggests that the ETV1 oncogenic program primes the prostate for disease progression following additional genetic lesions. Indeed, the combination of ETV1 overexpression and Pten reduction promoted progression of disease, and this was more frequent with a stronger AR allele. RNA-seq showed that ETV1 antagonism of AR was abrogated in neoplasia with reduced Pten, but in tumors AR was again repressed. Comparison to patient data revealed known and novel PCa-associated genes with potential ETV1 regulation.Benign human prostate cells, as well as PCa cells harboring ETV1 overexpression with or without PTEN loss, were used to model PCa progression in vitro. In malignant cells ETV1 consistently antagonized the same key AR targets as in mouse tissue, but in benign cells cooperation as well as repression was shown. These experiments highlight the interdependent relationships of the androgen axis, oncogene activation and tumor suppressor loss in PCa, revealing multiple pathways that should be considered simultaneously in future research and therapy.