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The Lipid Trigger: Metabolic Rewiring and the Path to Early Breast Tumorigenesis

While breast cancer mortality rates are generally decreasing across the globe, incidence rates continue to rise (1). This highlights the urgent need to understand breast cancer etiology, which can lay the foundation for preventative or early intervention measures. A recent Science Advances paper explores the early cellular changes that occur in non-transformed breast cells that may contribute to tumorigenesis (2). This study spotlights the link between the de novo serine pathway and the early cellular changes in estrogen receptor-negative (ERneg) breast cancer, mediated by the enzyme phosphoglycerate dehydrogenase (PHGDH).

Mariana Bustamante Eduardo, PhD

The study was led by Mariana Bustamante Eduardo, PhD, a postdoctoral fellow in the laboratories of Susan Clare, MD, PhD, and Seema Khan, MD, at Northwestern University. Dr. Bustamante Eduardo received the 2023 AACR-Pfizer Breast Cancer Research Fellowship for her work linking lipid metabolism, epigenetic reprogramming, and ERneg breast cancer oncogenesis. Speaking on the implications of the study, she shared, “By uncovering a lipid-driven mechanism of metabolic and epigenomic transformation in normal cells, our work contributes to a growing recognition that cancer metabolism is not only a feature of established tumors but also involved in the genesis of breast cancer and subtype specification.”

Prior work from her research group identified an enrichment of a lipid metabolism gene signature in the contralateral, unaffected breast of women with ERneg breast cancer. These studies also revealed increased flux through several metabolic reactions, particularly the serine, one-carbon, glycine (SOG) and methionine pathways (3-5). Metabolic networking modeling suggested that this increase was due to a shift from glycolysis to the de novo serine pathway, and the research published in Sciences Advances aimed to test this hypothesis.

Laboratories of Susan Clare, MD, PhD, and Seema Khan, MD

Dr. Bustamante Eduardo and her colleagues exposed ERneg MCF-10A breast epithelial cells and normal tissue-derived breast microstructures to octanoic acid (OA), a medium-chain fatty acid. In MCF-10A cells, U13C-glucose tracing revealed that glucose carbons were diverted to the de novo serine pathway. This effect was blocked by CBR-5884, a small molecule inhibitor of PHGDH, the rate-limiting enzyme in the de novo serine pathway. OA exposure also elevated mitochondrial and nuclear reactive oxygen species (ROS), likely due to fatty acid oxidation, leading to increased DNA damage. In response, MCF-10A cells increased levels of the antioxidant glutathione to mitigate ROS levels, allowing a subset of cells to survive despite DNA damage occurrence. Using tissue-derived breast microstructures, inhibiting the de novo serine pathway blocked the effects of OA-induced gene expression, supporting that the metabolic shift towards the de novo serine pathway occurs in cellular environments resembling complex breast tissue.

In addition to a robust increase in S-Adenosylmethionine, a key cellular methyl donor, OA-induced activation of PHGDH elevated the levels of 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits histone demethylases. To interrogate the impact of OA exposure on the histone methylation landscape, the team performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing for H3K4me3, a transcriptionally active mark. Pathway analysis of OA-induced genes associated with H3K4me3 enrichment revealed neural-related pathways as among the most affected. Consistent with this, OA-exposed MCF-10A and primary breast cells adopted a neural-like phenotype when cultured under standard neural cell conditions. Overall, these findings suggest that OA induces phenotypic plasticity in non-transformed breast epithelial cells through epigenetic reprogramming.

“Critically, these changes occur in non-transformed breast cells and tissue, suggesting that metabolic dysregulation and epigenetic remodeling may be early events in the initiationof ERneg breast cancer. The central role of PHGDH—the first and rate-limiting enzyme in the de novo serine pathway, which is consistently overexpressed in ERneg tumors—further links our findings to known oncogenic pathways and underscores its potential as a target for early intervention,” Dr. Bustamante Eduardo shared.

The AACR-Pfizer Breast Cancer Research Fellowship provided Dr. Bustamante Eduardo with access to the resources needed to complete the metabolic, transcriptomic, and epigenomic analyses. However, Dr. Bustamante Eduardo acknowledged that the benefits of this grant extend past the laboratory. “Beyond the scientific impact, this grant created opportunities to build meaningful personal connections and engage in rich scientific discussions—both in person and virtually,” she explained. “I am forever grateful for the support.”

References

  1. Kim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med 2025;31(4):1154-1162. doi: 10.1038/s41591-025-03502-3.
  2. Bustamante Eduardo M, Cottone G, McCloskey CW, Liu S, Palma FL, Paula Zappia M, et al. A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells. Sci Adv 2025;11(12):eads9182. doi:  10.1126/sciadv.ads9182.
  3. Wang J, Scholtens D, Holko M, Ivanic D, Lee O, Hong H, et al. Lipid metabolism genes in contralateral unaffected breast and estrogen receptor status of breast cancer. Cancer Prev Res 2013;6(4):321-30. doi: 10.1158/1940-6207.CAPR-12-0304
  4. Wang J, Shidfar A, Ivanic D, Ranjan M, Liu L, Choi M, et al. Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer. Int J Cancer 2017;140(11):2484-2497. doi: 10.1002/ijc.30680.
  5. Yadav S, Virk R, Chung CH, Bustamante Eduardo M, VanDerway D, Chen D, et al. Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer. NPJ Breast Cancer 2022;8(1):59. doi: 10.1038/s41523-022-00422-0