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 New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience

nachricht Wintering ducks connect isolated wetlands by dispersing plant seeds
22.02.2017 | Utrecht 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: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Positrons as a new tool for lithium ion battery research: Holes in the electrode

22.02.2017 | Power and Electrical Engineering

New insights into the information processing of motor neurons

22.02.2017 | Life Sciences

Healthy Hiking in Smart Socks

22.02.2017 | Innovative Products

VideoLinks
B2B-VideoLinks
More VideoLinks >>>