Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Amplification of a Stat5 gene produces excess oncogenic protein that drives prostate cancer spread

08.05.2013
An international group of investigators, led by researchers at Thomas Jefferson University's Kimmel Cancer Center, have solved the mystery of why a substantial percentage of castrate-resistant metastatic prostate cancer cells contain abnormally high levels of the pro-growth protein Stat5.

They discovered that the gene that makes the protein is amplified — duplicated many times over — in these cancer cells, which allows them to produce excess amounts of the oncogenic protein.

The study, reported in the May 7 issue of the American Journal of Pathology, found a direct association between the number of Stat5 genes in human prostate cancer cells and Stat5 protein levels, and also revealed that gene amplification and protein levels increased as prostate cancer metastasized and became resistant to castration (anti-androgen) therapy.

The finding is important since agents that inhibit the Stat5 pathway are currently entering clinical trials, says the study's senior author, Marja Nevalainen, M.D., Ph.D., associate professor of Cancer Biology, Medical Oncology, and Urology at Jefferson.

"Our latest findings on Stat5 provide further support for the idea that targeting Stat5 protein pharmacologically might provide powerful therapy for advanced prostate cancer," she says. "Our hope is that a successful agent might prevent some prostate tumors from spreading and might be able to contain metastasis that has already occurred and become castrate-resistant."

The discovery also suggests that testing Stat5 gene amplification in patients could provide a biomarker that identifies those patients most likely to respond to Stat5 inhibition, Dr. Nevalainen says.

Not only is Dr. Nevalainen testing Stat5 inhibitors developed by Astra Zeneca and Novartis in preclinical studies, her lab has also developed its own inhibitor, which is also being tested.

Dr. Nevalainen has long studied Stat5 in prostate cancer, and with her colleagues, has authored a number of crucial studies demonstrating the impact the gene and its protein can have on prostate cancer progression. "Stat5 isn't the only protein that drives prostate cancer, but it is a very important one," she says.

Stat5 is a transcription factor – a protein that can regulate expression of other genes. In 2003, Dr. Nevalainen discovered that Stat5 protein is critical for viability of prostate cancer cells and growth of prostate tumors in mice. In 2004, Dr. Nevalainen found that Stat5 inside a cell's nucleus is often over-expressed in high-grade human prostate cancer, and in 2005, she demonstrated that Stat5 activity was associated with recurrence of prostate cancer in patients who had already been treated. Then, in 2008 she showed that nuclear Stat5 was especially prevalent in recurrent prostate cancers that are resistant to hormone therapy. Most importantly, her research has demonstrated that blocking Stat5 in laboratory and in animal models effectively destroyed prostate cancer. "We know that Stat5 is absolutely critical to the survival of prostate cancer cells," she says.

In 2010, Dr. Nevalainen found that excess Stat5 in prostate cancer cells is linked to metastasis, and excess Stat5 expression predicts early disease recurrence and death from prostate cancer. This study was conducted to investigate why such over-expression of the protein occurs.

The researchers found amplification of the Stat5 gene in a significant fraction of 128 prostate cancer specimens from patients, and that Stat5 gene amplification was more frequently found in metastatic cancers that are no longer responsible to castration treatment (29 percent) and in high histological grade cancers (40 percent). Experiments in cell culture and in mice showed that increased Stat5 copy numbers conferred a growth advantage for tumors.

"Lots of cancers have chromosomal rearrangements that lead to amplification of pro-growth genes," says Dr. Nevalainen. "We don't know exactly why this happens, but it is related to imperfect cell division and unstable genomes."

While it is known that excess Stat5 protein predicts early recurrence of prostate cancer, development of metastatic disease and death from prostate cancer, researchers will need to determine if Stat5 gene amplification is also linked to those outcomes, she adds.

Researchers who contributed to the study included investigators from Georgetown University, the University of Helsinki in Finland, the University of Basel in Switzerland, and the University of Tampere in Finland. The authors declare no conflicts of interest.

The work was supported by grants from the National Institutes of Health, and the Academy of Finland.

Thomas Jefferson University (TJU), the largest freestanding academic medical center in Philadelphia, is nationally renowned for medical and health sciences education and innovative research. Founded in 1824, TJU includes Jefferson Medical College (JMC), one of the largest private medical schools in the country and ranked among the nation's best medical schools by U.S. News & World Report, and the Jefferson Schools of Nursing, Pharmacy, Health Professions, Population Health and the Graduate School of Biomedical Sciences. Jefferson University Physicians is TJU's multi-specialty physician practice consisting of the full-time faculty of JMC. Thomas Jefferson University partners with its clinical affiliate, Thomas Jefferson University Hospitals.

Jackie Kozloski | EurekAlert!
Further information:
http://www.jefferson.edu

More articles from Health and Medicine:

nachricht On track to heal leukaemia
18.01.2017 | Universitätsspital Bern

nachricht Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>