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

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>