Northwestern Medicine investigators have discovered previously unknown metabolic changes that may contribute to the development of estrogen receptor–negative (ERneg) breast cancer, according to recent findings published in Science Advances.

The study, led by Susan Clare, ’90 MD, ’88 Ph.D., research associate professor of Surgery, and Seema Khan, MD, the Bluhm Family Professor of Cancer, has the potential to inform new targeted preventives and therapeutics for patients who currently have limited treatment options.

Mariana Bustamante Eduardo, Ph.D., a postdoctoral fellow in the Khan/Clare laboratory, was lead author of the study.

According to the National Cancer Institute, roughly 15% of breast cancer cases are hormone-receptor negative, in which breast cancer cells do not contain hormone (estrogen or progesterone) receptors. These receptors attach to certain hormones in the blood and help the cancer cells grow.

Hormone-receptor negative breast cancer, which includes estrogen receptor–negative (ERneg) breast cancer, typically does not respond well to hormone therapy, leaving patients with few treatment options.

Previous work led by Khan had discovered that in patients with ERneg breast cancer, epithelial cells from unaffected, healthy breast tissue in the breast opposite of the cancerous breast had increased expression of a lipid metabolism gene signature.

They also found that lipids redirect metabolism to the serine, one-carbon, glycine (SOG) pathway, which is significantly associated with the development of ERneg breast cancer, and the methionine pathway, which affects protein methylation.

In the current study, the investigators used metabolomics, epigenomic profiling and single-cell RNA sequencing approaches to study human breast epithelial cell lines and healthy breast tissue samples that had been exposed to medium-chain fatty acids.

“The changes that happen with the fat exposure, the changes in metabolism and the changes in histone methylation and gene expression are the types of changes that can be associated with hormone-receptor negative breast cancer. They’re pertinent to what we see in actual tumors that happen in humans,” said Khan, who is also a professor of Surgery in the Division of Breast Surgery and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Using such techniques, the scientists were able to identify a link between lipid metabolism and ERneg breast cancer through an enzyme called phosphoglycerate dehydrogenase (PHGDH). When medium-chain fatty acids are present, the cells’ metabolism shifts toward the SOG and methionine pathways.

They also discovered that PHGDH helps increase the production of S-adenosylmethionine, which helps regulate gene expression via methylation, and the production of an oncometabolite called 2-hydroxyglutarate, which leads to epigenomic reprogramming in the breast epithelial cells.

Additionally, this metabolic shift increased the antioxidant glutathione, which reduces reactive oxygen species molecules and, therefore, promotes the survival of cells that have undergone DNA damage from oxidative stress.

According to the authors, the findings align with several hallmarks of cancer, including deregulated cellular metabolism, cell death resistance and non-mutational epigenomic reprogramming, mechanisms that may help inform new preventive treatments for patients.

“Where we are hoping this will all lead is to identify both ways of predicting that an individual woman is at increased risk of ER-negative cancer specifically and that it may lead to preventive interventions,” Khan said.