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. Copyright © 2013 American Society for Investigative Pathology.

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; Fortina, Paolo; Adam, Ertel; Chengbao, Liu; Hallgeir, Rui; Tapio, Visakorpi; Lukas, Bubendorf; Costas D., Lallas; Edouard J., Trabulsi; Peter, Mccue; Leonard, Gomella; Marja T., Nevalainen. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - STAMPA. - 182:6(2013), pp. 2264-2275. [10.1016/j.ajpath.2013.02.044]

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

FORTINA, PAOLO;
2013

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. Copyright © 2013 American Society for Investigative Pathology.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/556789
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