Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Health

Background:

• Obesity is a known risk factor for invasive breast cancer.
• The molecular differences between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) in obese individuals are not well understood.

Purpose of the Study:

• To investigate the molecular heterogeneity of DCIS and IDC in obese versus non-obese patients.
• To identify distinct transcriptional signatures associated with obesity in the tumor microenvironment.

Main Methods:

• Spatially resolved transcriptomics was used to profile epithelial, stromal, and immune cells.
• Lesions were stratified by body mass index (BMI) into non-obese (≤29.9 kg/m²) and obese (≥30 kg/m²) categories.

Main Results:

• In non-obese patients, IDC showed increased proliferation and epithelial-to-mesenchymal transition compared to DCIS.
• Obese patients displayed a distinct 'stress-adaptive' phenotype in IDC, with enriched metabolic adjustment, oxidative stress, and inflammation.
• The obese tumor microenvironment featured a fibro-inflammatory stroma, immunosuppression (B cell depletion, M2 macrophage enrichment), and upregulation of SULF2.

Conclusions:

• Obesity drives an alternative invasive transcriptional program in breast cancer, distinct from classical proliferative drivers.
• Standard prognostic markers may be context-dependent in obese individuals.
• Metabolic health should be integrated into precision risk stratification for breast cancer.