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Study Finds Novel Molecular Mechanism for Breast Cancer Cell Metabolism and Survival

A study from the Department of Biochemistry and Molecular Biology at Drexel University College of Medicine offers a potential new therapy for difficult-to-treat breast cancers. A team of investigators discovered that targeting a specific enzyme can kill triple-negative breast cancer cells, but spare non-tumor cells as well. The study appears in the June 5, 2014, edition of Molecular Cell.

Mauricio J. Reginato, PhD"Breast cancer is the world's leading cancer in women, and the triple-negative breast cancer subtype is the deadliest and most difficult to treat since there is no targeted therapy currently available," said the study's lead investigator Mauricio J. Reginato, PhD, associate professor in the Department of Biochemistry and Molecular Biology. "We hope this novel discovery may aid in developing new treatment protocols."

The team discovered that O-GlcNAc transferase (OGT), an enzyme that adds sugars to a number of nuclear and cytosolic proteins, is essential for allowing cancer cells to switch to glycolysis for energy demands. OGT regulates degradation of the hypoxia-inducible factor 1 (HIF-1a), a critical driver of cancer cell metabolism. Importantly, the study shows that reducing levels of OGT or blocking OGT activity with a small molecule selectively induced metabolic stress and cell killing in cancer cells but not in non-cancer breast cells. By profiling hundreds of metabolites, the team discovered that blocking OGT in tumor cells reduces critical metabolites involved in energy production that feeds cancer growth and survival. The authors also discovered that regulation of a particular metabolite — alpha-ketoglutarate, a critical cofactor for HIF-1a degradation — is one mechanism by which OGT regulates HIF-1a.

The team showed that this tumor subtype contains higher expression of OGT and HIF-1a compared to other breast cancer subtypes. These results provide evidence that targeting OGT in difficult-to-treat triple-negative breast cancer may provide a future therapeutic option.

The members of the research team included: lead author Christina Ferrer and Valeria Sodi, both PhD candidates in the Molecular and Cell Biology and Genetics program; medical student John Falcone; and former student Thomas Lynch, PhD. This research is supported by National Cancer Institute R01 and F31 grants, and past CURE grants. This work also included collaborators from the University of Tennessee and Simon Fraser University in Canada.



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