STAT5A/B gene locus undergoes amplification during human prostate cancer progression.
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.
Published In/Presented At
Haddad, B. R., Gu, L., Mirtti, T., Dagvadorj, A., Vogiatzi, P., Hoang, D. T., 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, C. D., Trabulsi, E. J., … Nevalainen, M. T. (2013). STAT5A/B gene locus undergoes amplification during human prostate cancer progression. The American journal of pathology, 182(6), 2264–2275. https://doi.org/10.1016/j.ajpath.2013.02.044
Medicine and Health Sciences
Department of Pathology and Laboratory Medicine