Jessica Kieu, MD
Breast Surgical Oncology Fellow
UCLA
Los Angeles, California, United States
Isabel Eng, n/a
UCLA
Los Angeles, California, United States
Peggy Sullivan, MD
UCLA
Los Angeles, California, United States
Jitin Makker, MD
UCLA
Los Angeles, California, United States
Miquel Ensenyat-Mendez, n/a
Duke
Durham, North Carolina, United States
Andrés F. Bedoya-López, MSc (he/him/his)
Bioinformatics & Biostatistics / Biomedical Research in Cancer
Fundación Instituto de Investigación Sanitaria Islas Baleares (IdISBa)
Palma, Islas Baleares, Spain
Julie Steele, MD
Scripps Health
La Jolla, California, United States
Sunil Kurian, PhD
Scripps Health
La Jolla, California, United States
Diego M. Marzese, PhD (he/him/his)
Research Scientists
Duke Cancer Institute
Durham, North Carolina, United States
Maggie L. DiNome, MD
Breast Surgical Oncologist
Duke University
Durham, North Carolina, United States
Jennifer Lynn Baker, MD
Associate Professor of Surgery
UCLA
Los Angeles, California, United States
Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancers and is associated with a higher risk of metastasis and death compared to other breast cancer subtypes. Obesity has been linked to the development of TNBC and poorer clinical outcomes, potentially through pro-inflammatory signaling and altered tumor microenvironments. However, the contribution of epigenetic mechanisms to obesity-associated TNBC remains unclear.
Methods:
We retrospectively identified 55 treatment-naïve TNBC patients from three institutions with available body mass index data and high-quality DNA methylation profiles. Patients were classified as obese (n=17) or non-obese (n=38) using WHO guidelines. Genome-wide DNA methylation was assessed using the Infinium Methylation EPIC v2.0 BeadChip; data were normalized using the R package ChAMP. Expression methylation quantitative trait loci (emQTLs) were obtained from Ankill et al. (2022), HiTIMED was used for tumor immune microenvironment deconvolution, and clusterProfiler was used for pathway enrichment analysis. Ki-67 data was examined in a subset of patients (n=48).
Results:
A total of 871,358 CpG sites were analyzed to assess DNA methylation levels in obese and non-obese patients with TNBC. Obese patients had global DNA hypomethylation compared with non-obese patients, with 17,543 hypomethylated and 1,419 hypermethylated CpG sites identified. Hypomethylated loci were enriched in emQTLs regulating the cell cycle, suggesting increased proliferative potential. Promoter hypomethylation of NR1H3 and hypomethylation at liver X receptor (LXR) binding sites, a transcription factor linked to increased proliferation, suggest transcriptional activation linked to obesity and cancer cell proliferation. Concordantly, TNBC tumors from obese patients had significantly increased Ki-67 expression compared to non-obese patients; interestingly, immune profiling also revealed reduced memory B-cells and epigenetic deregulation of B-cell–related pathways.
Conclusions:
Obesity is associated with global DNA hypomethylation, activation of proliferative pathways, and impairment of B-cell-mediated immune responses in patients with TNBC. Consistent with these findings, obese patients demonstrated higher Ki-67 expression, reflecting more aggressive tumor characteristics. These findings highlight potential mechanisms underlying poorer outcomes in obese patients with TNBC and support the need for further investigation into obesity-driven epigenetic regulation of breast cancer progression.