STAT5A/B gene locus undergoes amplification during human prostate cancer progression

Bassem R. Haddad, Lei Gu, Tuomas Mirtti, Ayush Dagvadorj, Paraskevi Vogiatzi, David T. Hoang, Renu Bajaj, Benjamin Leiby, Elyse Ellsworth, Shauna Blackmon, Christian Ruiz, Mark Curtis, Paolo Fortina, Adam Ertel, Chengbao Liu, Hallgeir Rui, Tapio Visakorpi, Lukas Bubendorf, Costas D. Lallas, Edouard J. TrabulsiPeter McCue, Leonard Gomella, Marja T. Nevalainen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2264-2275
Number of pages12
JournalAmerican Journal of Pathology
Volume182
Issue number6
DOIs
Publication statusPublished - Jun 1 2013
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Haddad, B. R., Gu, L., Mirtti, T., Dagvadorj, A., Vogiatzi, P., Hoang, D. T., ... Nevalainen, M. T. (2013). STAT5A/B gene locus undergoes amplification during human prostate cancer progression. American Journal of Pathology, 182(6), 2264-2275. https://doi.org/10.1016/j.ajpath.2013.02.044