Researchers from the University of Cincinnati (UC) and Cincinnati Children’s Hospital Medical Center studying the biology of breast cancer recurrence, report they have identified a metabolic signature that predicts outcomes and opens potential therapeutic targets.

The new findings are published in the journal PLOS ONE in a study titled,NMR-based metabolomic analysis identifies RON-DEK-β-catenin dependent metabolic pathways and a gene signature that stratifies breast cancer patient survival,” which was led by UC’s Susan Waltz, PhD, and Cincinnati Children’s Susanne Wells, PhD.

“Advances in detection techniques and treatment have increased the diagnosis of breast cancer at early stages; however, recurrence occurs in all breast cancer subtypes, and both recurrent and de novo metastasis are typically treatment resistant,” wrote the researchers.

Waltz said the collaboration with Wells’ lab began around 15 years ago, as both research groups were studying different oncogenes called Ron and DEK.

“We showed that both Ron and DEK are very important in breast cancer and that both Ron and DEK are independently associated with poor overall survival in breast cancer patients,” said Waltz, a professor in the department of cancer biology at UC’s College of Medicine and a University of Cincinnati Cancer Center member. “We know that Ron and DEK as genes are very important in predicting breast cancer recurrence, but there are not great drugs yet that can target at least DEK right now.”

The current study focused on the role of how metabolism in the body is constantly changing, which plays a significant role in how cancer grows and recurs.

“Our metabolism is ever-changing based on how we are designed genetically and also based on what we ingest and are exposed to,” said Wells, a professor in the UC department of pediatrics, director of the Epithelial Carcinogenesis and Stem Cell Program at Cincinnati Children’s, and a Cancer Center member. “And cancer cells love a certain metabolism that is called a cancer metabolism and promotes cancer formation and spread.”

The researchers found that the Ron and DEK genes can regulate certain metabolites.

“So we went about and found changes in metabolites, and then took those changes and went back and figured out which enzymes were involved in regulating those metabolites,” Waltz said.

“We can use those metabolic pathways to understand how we might be able to better treat cancer patients so that they’re not more susceptible to breast cancer recurrence,” Waltz added. “It could be dietary, it could be different ways of treating patients compared to the toxic drugs that we give patients now.”

“Regulating metabolites is much easier than regulating genes,” Wells said. “Now we are really opening up a path that is much wider than just targeting Ron and DEK. Hopefully, someday we can treat these worst features of cancer by targeting cancer metabolism.”

Waltz said further research will include looking at how Ron and DEK affect other molecules such as lipids, or fatty acids, that also play a role in metabolism. By further defining more specific metabolic signatures that align with breast cancer patient outcomes, even more avenues for new treatments may be found.

“In other words, which metabolite is most important in driving these poor outcomes and how do we target it,” Wells said.

“The RON-DEK-β-catenin axis regulates the numerous metabolic pathways with significant associations to breast cancer patient outcomes,” concluded the researchers.

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