Obesity-linked leptin drives DNA hypomethylation in breast epithelial cells

Obesity has long been recognized as a risk factor for breast cancer, but the molecular steps connecting excess body weight to malignant transformation remain incompletely mapped.

The research team, led by Hana Triki and Pierre-François Cartron, reports that leptin is associated with global DNA hypomethylation, a widespread loss of methyl marks across the genome. The authors identify this leptin-induced hypomethylation as a pro-oncogenic event.

The study examined women without cancer and found that plasma leptin levels correlate with the degrees of methylation, hydroxymethylation, and oxidation of cell-free circulating DNA, the fragments of DNA that circulate in the bloodstream. The same pattern appeared when breast epithelial cells were exposed to leptin in the laboratory, suggesting that the hormone itself can drive these epigenetic changes.

At the molecular level, the researchers traced the effect to two converging mechanisms. Cells exposed to elevated leptin lost expression of DNMT1 and DNMT3B, enzymes responsible for establishing and maintaining DNA methylation. At the same time, the cells showed a gain of TET1/OGG1 interaction. Together, the loss of methylating enzymes and the gain of the TET1/OGG1 interaction produced global hypomethylation alongside hyperhydroxymethylation and hyperoxidation of DNA.

These epigenetic shifts were not randomly distributed across the genome. Among the affected genes were TBX3, LRP6, occludin, and claudin-7 (CLDN7), all of which have been linked to EMT-associated processes.

A crucial caveat accompanies these findings: elevated leptin alone was not sufficient to induce tumor formation. The authors emphasize that the hypomethylation they observed is moderate in intensity and is not tumorigenic by itself. Instead, they propose that it may act as a priming event, preparing the epigenetic ground on which subsequent oncogenic insults could act.

The study also offers a potential intervention strategy. This observation raises the possibility that nutritional supplementation could be evaluated as a preventive measure in women whose leptin-driven epigenetic changes place them at elevated risk.

Beyond the mechanistic findings, the work carries a translational proposal: measuring DNA hypomethylation in cell-free circulating DNA as a new biomarker. According to the authors, such a marker could be used to stratify women according to their risk of developing breast cancer and to evaluate whether preventive interventions, including folic acid and caffeic acid supplementation, succeed in limiting global DNA hypomethylation.

The study arrives against a sobering backdrop. Although risk factors for breast cancer are well characterized, more than two million cases are still diagnosed worldwide each year, a figure the authors cite as motivation for identifying the molecular pathways that confer risk. Characterizing these pathways, they argue, is an urgent step toward molecular biomarkers and strategies for interventional and preventive medicine.

As with any cell-based and correlative study, the findings describe associations and mechanisms observed in specific experimental models rather than demonstrated outcomes in patients. The authors themselves frame the leptin-induced hypomethylation as a moderate, non-tumorigenic priming event rather than a direct cause of cancer. Whether the proposed biomarker performs in clinical settings, and whether epinutrient supplementation can meaningfully modify risk, will require further investigation. The article was published open access on 21 September 2026 as an early, peer-reviewed version subject to further edits before the final Version of Record.

Subject of Research: Leptin-induced DNA hypomethylation and EMT gene changes in breast epithelial cells as a potential breast cancer risk mechanism

Article Title: Leptin levels associated with obesity induce global DNA hypomethylation increasing EMT-associated genes expression in breast epithelial mammary cells

Article References: Triki, H., Bougras-Cartron, G., Roussel, A., Charrier, C., Lamoureux, F., Ory, B., Dehours, C., Vidi, P.-A., & Cartron, P.-F. (2026). Leptin levels associated with obesity induce global DNA hypomethylation increasing EMT-associated genes expression in breast epithelial mammary cells. Breast Cancer Research. https://doi.org/10.1186/s13058-026-02391-9

Image Credits: AI Generated

DOI: 10.1186/s13058-026-02391-9

Keywords: leptin, obesity, breast cancer, DNA methylation, DNA hypomethylation, epithelial-mesenchymal transition, DNMT1, TET1, cell-free DNA, biomarker, epinutrients, folic acid