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STAT5A/B gene locus undergoes amplification during human prostate cancer progression. Am J Pathol 2013 Jun;182(6):2264-75

Date

05/11/2013

Pubmed ID

23660011

Pubmed Central ID

PMC3668029

DOI

10.1016/j.ajpath.2013.02.044

Scopus ID

2-s2.0-84878221509   26 Citations

Abstract

The molecular mechanisms underlying progression of prostate cancer (PCa) to castrate-resistant (CR) and metastatic disease are poorly understood. Our previous mechanistic work shows that inhibition of transcription factor Stat5 by multiple alternative methods induces extensive rapid apoptotic death of Stat5-positive PCa cells in vitro and inhibits PCa xenograft tumor growth in nude mice. Furthermore, STAT5A/B induces invasive behavior of PCa cells in vitro and in vivo, suggesting involvement of STAT5A/B in PCa progression. Nuclear STAT5A/B protein levels are increased in high-grade PCas, CR PCas, and distant metastases, and high nuclear STAT5A/B expression predicts early disease recurrence and PCa-specific death in clinical PCas. Based on these findings, STAT5A/B represents a therapeutic target protein for advanced PCa. The mechanisms underlying increased Stat5 protein levels in PCa are unclear. Herein, we demonstrate amplification at the STAT5A/B gene locus in a significant fraction of clinical PCa specimens. STAT5A/B gene amplification was more frequently found in PCas of high histologic grades and in CR distant metastases. Quantitative in situ analysis revealed that STAT5A/B gene amplification was associated with increased STAT5A/B protein expression in PCa. Functional studies showed that increased STAT5A/B copy numbers conferred growth advantage in PCa cells in vitro and as xenograft tumors in vivo. The work presented herein provides the first evidence of somatic STAT5A/B gene amplification in clinical PCas.

Author List

Haddad BR, Gu L, Mirtti T, Dagvadorj A, Vogiatzi P, Hoang DT, Bajaj R, Leiby B, Ellsworth E, Blackmon S, Ruiz C, Curtis M, Fortina P, Ertel A, Liu C, Rui H, Visakorpi T, Bubendorf L, Lallas CD, Trabulsi EJ, McCue P, Gomella L, Nevalainen MT

Authors

Marja T. Nevalainen MD, PhD Assistant Dean, Professor in the Pathology department at Medical College of Wisconsin
Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
DNA Copy Number Variations
DNA, Neoplasm
Disease Progression
Gene Amplification
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
Male
Mice
Mice, Nude
Neoplasm Grading
Neoplasm Transplantation
Prostatic Neoplasms
Recurrence
STAT5 Transcription Factor
Transplantation, Heterologous
Tumor Cells, Cultured
Tumor Suppressor Proteins
jenkins-FCD Prod-399 190a069c593fb5498b7fcd942f44b7bc9cdc7ea1