Altered Metabolic Pathway In ER-Negative Breast Cancer May Provide New Target for Treatment
There are several types of breast cancer, depending for instance on whether or not they express the protein that the female hormone estrogen binds to on the surface of the cancer cells. This protein is called estrogen receptor, or ER. Patients whose cancer cells do not express this protein, that is they have ER-negative tumors, have a worse prognosis than patients with ER-positive breast tumors.
Metabolism is how the cells of our body get their energy from oxygen: this involves a series of complex chemical reactions at the cellular level. Cancer cells divide very fast and need energy much faster than normal cells; they modify their surroundings to enable the fuel they need to reach them more quickly, and they use anaerobic metabolism, without oxygen, to do it.
Thus studying ways in which cancer cells get hold of their fuel could lead to targets for new drugs that interfere with this process and potentially cut off the supply and starve the cancer cells.
Cancer metabolism as a field of study is not new: in the 1940s a scientist called Otto Warburg noticed that rapidly dividing cancer cells didn't use oxygen in the same way as cells that divide normally. But as often happens in science, this was overtaken by events, such as the discovery of DNA.
So, it was not until more recently, that interest in Warburg and his earlier work has reawakened. Recent research in cancer metabolism has found for instance that cancer cells become addicted to certain fuel sources and metabolic pathways. For example, sugar metabolism (glycolysis) and fatty acid metabolism, as well as self-metabolism (autophagy) are three pathways found to be very important to cancer metabolism.
Also, with the help of new techniques developed in the field of genetic research, such as high throughput analysis, it is possible to screen lots of pathways at the same time and find candidate ones.
In this latest Nature study, scientists from Agios Pharmaceutical and the laboratory of David Sabatini (who is also on Agios' scientific advisory board) at the Whitehead Institute and Massachusetts Institute of Technology in the US, describe how they found an anomaly in the serine pathway, one of the metabolic pathways that helps ER-negative breast cancer cells to get their energy and multiply.
They used a high throughput method called "RNA interference (RNAi)-based loss-of-function screening" as their screening tool, because it had already "proven powerful for the identification of new and interesting cancer targets", including in live mice to find tumor suppressor genes.
So, using this method, they screened 133 metabolic genes linked to aggressive breast cancer to find those that the cancer was relying on to grow tumors. They did the in vivo screening on breast cancer tumors that had been grafted onto live mice.
One of the genes they identified was phosphoglycerate dehydrogenase (PHGDH). Proteins from this gene are found in much higher concentration in about 70% of ER-negative breast cancers, and it plays a role in cancer metabolism:
"PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux", write the authors.
The researchers then used other methods, metabolomics and metabolic flux analysis, to experiment with PHGDH in cancer cells.
One of the things they tried was to suppress the gene in cancer cells. They found, using cell lines with high levels of PHGDH expression, both cell proliferation serine synthesis decreased. This did not happen when they suppressed it in cell lines with low levels of expression.
The authors concluded that their study shows two things: it identifies dysregulation of the serine pathway as a potential target for treatment in certain breast cancers, and it demonstrates that in vivo negative-selection RNAi screens could be a powerful tool for investigating metabolic targets in cancer.
Senior author Sabatini said in a statement:
"We are thrilled to have identified a new potential metabolic pathway for breast cancer."
"This research strongly suggests a central role for metabolic pathways in driving the growth of certain breast cancer cells. The serine pathway, and in particular the enzyme PHGDH, present a promising area for further study in the search for new therapeutic targets in cancer," he added.
"Functional genomics reveal that the serine synthesis pathway is essential in breast cancer."
Richard Possemato, Kevin M. Marks, Yoav D. Shaul, Michael E. Pacold, Dohoon Kim, Kıvanç Birsoy,and others.
Nature, published online 14 July 2011, doi:10.1038/nature10350
Link to Abstract.
Additional sources: Agios, MIT, Cancer Research UK.
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