Obesity is a major modifiable factor associated with 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 population-attributable fraction of approximately 43% for TNBC—an effect size exceeding most previous reports. Family history was independently associated with TNBC. Mechanistically, primary mammary fibroblasts from obese donors downregulated ER-α and HER2 in human mammary epithelial cells, providing a plausible explanation for obesity-driven ER/HER2-negative tumorigenesis.

CONCLUSIONS

Obesity is a major, modifiable factor strongly associated with TNBC, with its effect magnified in high-risk populations. The mechanistic link to ER and HER2 suppression suggests a plausible biological pathway, highlighting metabolic health as a critical target for prevention strategies worldwide.