title: STAT5A/B gene locus undergoes amplification during human prostate cancer progression.
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.
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors: Bassem R
authors: BR
authors: Haddad
authors: Lei
authors: L
authors: Gu
authors: Tuomas
authors: T
authors: Mirtti
authors: Ayush
authors: A
authors: Dagvadorj
authors: Paraskevi
authors: P
authors: Vogiatzi
authors: David T
authors: DT
authors: Hoang
authors: Renu
authors: R
authors: Bajaj
authors: Benjamin
authors: B
authors: Leiby
authors: Elyse
authors: E
authors: Ellsworth
authors: Shauna
authors: S
authors: Blackmon
authors: Christian
authors: C
authors: Ruiz
authors: Mark
authors: M
authors: Curtis
authors: Paolo
authors: P
authors: Fortina
authors: Adam
authors: A
authors: Ertel
authors: Chengbao
authors: C
authors: Liu
authors: Hallgeir
authors: H
authors: Rui
authors: Tapio
authors: T
authors: Visakorpi
authors: Lukas
authors: L
authors: Bubendorf
authors: Costas D
authors: CD
authors: Lallas
authors: Edouard J
authors: EJ
authors: Trabulsi
authors: Peter
authors: P
authors: McCue
authors: Leonard
authors: L
authors: Gomella
authors: Marja T
authors: MT
authors: Nevalainen
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012008:Recurrence; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins
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