Obesity is a Dominant Driver of ER-Negative Breast Cancer: Epidemiological and Mechanistic Evidence from a High-Risk Cohort

Background The biological mechanisms linking modifiable risk factors to aggressive breast cancer subtypes remain poorly defined, particularly in underrepresented populations which experience a disproportionate burden. Regions with high obesity prevalence and early-onset disease provide a unique setting to investigate these drivers. Methods In a case-control study of 567 premenopausal breast cancer cases and 906 controls from a high-risk population, tumors were classified into molecular subtypes. Logistic regression estimated subtype-specific risks, and population-attributable fractions (PAF) were calculated. To provide mechanistic validation, we examined paracrine effects of fibroblasts from obese versus lean women on ER-α expression in breast epithelial cells using co-culture and qRT-PCR analysis. Results Obesity was the strongest modifiable factor, with adjusted ORs ranging from 2.29 (luminal B) to 4.32 (TNBC), corresponding to a PAF of 65.2% for TNBC—an effect size exceeding most previous reports. Family history was independently associated with TNBC. Mechanistically, fibroblasts from obese donors downregulated ER-α mRNA expression in malignant epithelial cells, providing a biologically coherent mechanism for obesity-driven ER-negative tumorigenesis. Conclusions Obesity is a dominant, actionable driver of TNBC, with its effect magnified in high-risk populations. The mechanistic link to ER suppression underscores a global biological pathway, highlighting metabolic health as a critical target for prevention strategies worldwide.