Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

CSHL team identifies enzyme that is an important regulator of aggressive breast cancer development

01.07.2011
PTPN23 can regulate the SRC oncoprotein; basis for a new therapeutic approach

Researchers at Cold Spring Harbor Laboratory (CSHL) have identified an enzyme that appears to be a significant regulator of breast cancer development. Called PTPN23, the enzyme is a member of a family called protein tyrosine phosphatases, or PTPs, that plays a fundamental role in switching cell signaling on and off.

When the scientists suppressed the expression of PTPN23 in human mammary cells, they noted a cascade of effects that included the cells breaking away from their anchors; their scattering; and their invasion through extracellular matrix (essentially, cells' mooring in tissue). These are the hallmarks of metastasis, the primary cause of mortality in cancer.

PTPs are able to affect cell signaling as a consequence of their very specific biochemical function: they remove phosphate groups from other molecules. Another family of enzymes, called kinases, does precisely the opposite: its members add phosphate groups, and in so doing, work together with the PTPs to regulate cell signaling.

CSHL Professor Nicholas Tonks, who purified the first PTP over 20 years ago, is an authority on phosphatases. He teamed up with CSHL Associate Professor Senthil Muthuswamy, an expert on kinases and breast cancer biology, who is also affiliated with the University of Toronto. They and their colleagues methodically suppressed each of the 105 known PTPs, in a cell culture system constructed to simulate mammary epithelial tissue. The cells were also modified so that the cancer-promoting receptor protein called HER2 (itself a kinase) could be activated selectively. Overabundant HER2 protein (also called ErbB2) is associated with aggressive disease and poor prognosis, and is found in about one-fourth of those who have breast cancer.

To determine the possible impact of PTPs on cancer development in cells expressing activated HER2, the team assembled a library of short-hairpin RNA molecules, or shRNAs, which had the ability to inactivate, one by one, the genes responsible for expressing each PTP. Of the 105 PTPs, they observed that three of them, when suppressed, were associated with increased motility, or the ability of the mammary cells to move freely of one another. The suppression of one of these three -- PTPN23 -- was also observed to cause the cells to become invasive.

Part of what makes this finding intriguing is the fact that the CSHL team was able to trace the cause of these effects to specific elements of a complex signaling cascade. And this, in turn, has led the team to identify a potentially powerful new therapeutic strategy in this aggressive cancer type.

They discovered that PTPN23, under normal conditions, i.e., when not suppressed, recognizes and removes phosphate groups from three molecules important in the signaling cascade in breast epithelial cells. These three molecules are called SRC, E-cadherin and â-catenin. Of the three, the key is SRC: it is a type of kinase that, like HER2, is well known to be a cancer-promoter. SRC-induced anomalies in cell signaling have been linked with breast and other cancer types.

Tonks, Muthuswamy and colleagues demonstrated for the first time that this particular PTP -- PTPN23 -- acts directly on SRC to inhibit its phosphate-adding activity. But when PTPN23 is suppressed, as in the team's experiments, SRC is free to add phosphates to other molecules in the cell, including E-cadherin and â-catenin. Normally, these molecules are important in cell adhesion. But when they are phosphorylated by SRC, their ability to function as the "glue" that holds cells to their anchors in epithelial tissue is impaired, and the cells are able to break free. This adds interest to the observation, made by others, that the gene that expresses PTPN23 is located within a "hotspot" on human chromosome 3 (3p21) that is mutated in breast and other cancers.

"Considering the negative effect of PTPN23 on SRC activity, loss of PTPN23 may promote tumor growth and metastasis in breast tumors that are associated with activation of SRC," the team suggests in a paper on the research published today in the journal Genes & Development.

This fine-grained picture of how an absence of PTPN23 can set in motion a chain of events in breast epithelial cells that promotes cancer proliferation in turn suggests the next step in the research. The team tried and was able to reverse the metastatic effects set in train by PTPN23 suppression in these cancer-cell models by introducing a candidate drug molecule called SU6656, which inhibits SRC.

On the theory that PTPN23 regulates the activity of SRC and the phosphorylation status of the E-cadherin/â-catenin signaling complexes to modulate cell motility, invasion and scattering, the team has moved to a new set of experiments in living mice which have been genetically engineered to lack PTPN23. In such animals, they expect aggressive tumors to form. They seek to address these by treating the mice with inhibitors of SRC.

"Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the 'PTP-ome'" appears July 1 in Genes & Development. The authors are: Guang Lin, Victoria Aranda, Senthil K. Muthuswamy and Nicholas K. Tonks. The paper can be obtained online at: http://www.genesdev.org/cgi/doi/10.1101/gad.2018911

About CSHL

Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 400 scientists strong and its Meetings & Courses program hosts more than 8,000 scientists from around the world each year. Tens of thousands more benefit from the research, reviews, and ideas published in journals and books distributed internationally by CSHL Press. The Laboratory's education arm also includes a graduate school and programs for undergraduates as well as middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island.

Peter Tarr | EurekAlert!
Further information:
http://www.cshl.edu

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>