Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Key metabolic pathway implicated in intractable form of breast cancer

19.07.2011
FINDINGS: Using a new in vivo screening system, Whitehead Institute researchers have identified a protein in a key metabolic pathway that is essential in estrogen receptor (ER)-negative breast cancer. When the expression of the gene that codes for this protein—phosphoglycerate dehydrogenase or PHGDH—is suppressed in tumors and cell lines with an overabundance of the protein, the rate of cellular growth declines markedly.

RELEVANCE: PHGDH is overexpressed in approximately 70% of ER-negative breast cancer patients. Patients with ER-negative disease respond poorly to treatment and have a low five-year survival rate. In cells and tumors where it is overexpressed, PHGDH may represent a promising target for drug development.

Using a new in vivo screening system, Whitehead Institute researchers have identified a protein in the serine biosynthesis pathway that is essential in estrogen receptor (ER)-negative breast cancer—a notoriously difficult disease to treat associated with low five-year survival rates.

According to the researchers, when expression of the gene that codes for this protein—phosphoglycerate dehydrogenase or PHGDH—is suppressed in tumors and cell lines with an overabundance of the protein, the rate of cellular growth declines markedly.

As reported this month in Nature, the in vivo screen focused on 133 metabolic genes that the researchers predicted to be necessary for tumorigenesis. Using RNA interference (RNAi), first author Richard Possemato targeted these genes in human breast cancer cells implanted in mice.

"Our goal for this study was to look for essential cancer genes in vivo, where the levels of metabolites are likely more appropriate than in an in vitro model system," says Possemato, a postdoctoral researcher in the lab of Whitehead Member David Sabatini.

In vivo screening provides a more realistic understanding of what would work in a living organism rather than in a Petri dish's artificial environment. During the screen Possemato and colleagues identified PHGDH, which is overexpressed in approximately 70% of ER-negative breast cancer patients, as essential to tumor growth. The PHGDH protein is one of three enzymes involved in the metabolic serine biosynthesis pathway. Cancer cells alter their metabolism in the interest of sustaining rapid growth, and high levels of PHGDH appear to drive such metabolic change. When Possemato suppressed PHGDH protein production in breast cancer cell lines with elevated levels of it, the cells stopped proliferating.

The findings suggest that PHGDH may represent a promising target for drug development for ER-negative breast cancer.

"We do think this has some therapeutic relevance, where an inhibitors of this enzyme would have effects on the cells we identified that tend to overexpress this enzyme," says Sabatini, who is also a biology professor at MIT. "By RNAi, we've provided proof of principle, but whether a drug against this protein would be valuable remains to be determined."

This research was supported by Susan G. Komen for the Cure, Life Science Research Foundation, Keck Foundation, David H. Koch Institute for Integrative Cancer Research at MIT, The Alexander and Margaret Stewart Trust Fund, and National Institutes of Health (NIH).

Sabatini serves as a Member of the Scientific Advisory Board of Agios Pharmaceuticals.

Written by Nicole Giese

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Functional genomics reveal that the serine synthesis pathway is essential in breast cancer"

Nature, online July 14, 2011.

Richard Possemato (1,2,3,4), Kevin M. Marks (5), Yoav D. Shaul (1,2,3,4), Michael E. Pacold (1,2,3,4,6), Dohoon Kim (1,2,3,4), Kývanç Birsoy (1,2,3,4), Shalini Sethumadhavan (5), Hin-KoonWoo (5), Hyun G. Jang (5), Abhishek K. Jha (5), Walter W. Chen (1,2,3,4), Francesca G. Barrett (1), Nicolas Stransky (3), Zhi-Yang Tsun (1,2,3,4), Glenn S. Cowley (3), Jordi Barretina (3,7), Nada Y. Kalaany (1,2,3,4), Peggy P. Hsu (1,2,3,4), Kathleen Ottina (1,2,3,4), Albert M. Chan (1,2,3,4), Bingbing Yuan (1), Levi A. Garraway (3,7), David E. Root (3), Mari Mino-Kenudson (8), Elena F. Brachtel (8), Edward M. Driggers (5) and David M. Sabatini (1,2,3,4).

1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
2. Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
3. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
4. The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
5. Agios Pharmaceuticals, 38 Sidney Street, Cambridge, Massachusetts 02139, USA.
6. Harvard Radiation Oncology Program, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02114, USA.
7. Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

8. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

Nicole Giese | EurekAlert!
Further information:
http://www.wi.mit.edu

More articles from Life Sciences:

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

nachricht CWRU researchers find a chemical solution to shrink digital data storage
22.06.2017 | Case Western Reserve University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

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)...

Im Focus: Optoelectronic Inline Measurement – Accurate to the Nanometer

Germany counts high-precision manufacturing processes among its advantages as a location. It’s not just the aerospace and automotive industries that require almost waste-free, high-precision manufacturing to provide an efficient way of testing the shape and orientation tolerances of products. Since current inline measurement technology not yet provides the required accuracy, the Fraunhofer Institute for Laser Technology ILT is collaborating with four renowned industry partners in the INSPIRE project to develop inline sensors with a new accuracy class. Funded by the German Federal Ministry of Education and Research (BMBF), the project is scheduled to run until the end of 2019.

New Manufacturing Technologies for New Products

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

A new technique isolates neuronal activity during memory consolidation

22.06.2017 | Life Sciences

Plant inspiration could lead to flexible electronics

22.06.2017 | Materials Sciences

A rhodium-based catalyst for making organosilicon using less precious metal

22.06.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>