Background:
Triple-negative breast cancer (TNBC) is an aggressive subtype with limited options for prevention and poor clinical outcomes. The biological pathways linking modifiable metabolic risk to receptor-negative breast cancer remain poorly defined. Populations with high obesity prevalence and early-onset disease offer a critical lens to quantify this risk and elucidate underlying mechanisms relevant to global cancer prevention.

Objectives:
To quantify the population-level impact of obesity on TNBC risk and to experimentally investigate stromal-mediated mechanisms linking metabolic dysfunction to hormone receptor loss.

Methods:
We conducted a case–control study including 567 premenopausal breast cancer cases and 906 controls. Tumors were classified into molecular subtypes using standardized immunohistochemical criteria for estrogen receptor (ER), progesterone receptor (PR), and HER2. Multivariable logistic regression models estimated subtype-specific odds ratios (ORs) for obesity, adjusting for key reproductive and familial factors, and population-attributable fractions (PAFs) were calculated to quantify preventable risk. Mechanistic studies used primary mammary fibroblasts from obese and non-obese donors in co-culture with breast epithelial cells to assess stromal-mediated effects on the expression of ER-α and HER2 coding genes using immunoblotting and quantitative RT-PCR.

Results:
Obesity emerged as the strongest modifiable risk factor for ER-negative disease, with a particularly strong association for TNBC (adjusted OR 4.32; 95% CI 2.52–7.42). An estimated 43% of TNBC cases were attributable to obesity, indicating a substantial preventable burden. Mechanistic experiments demonstrated that fibroblasts derived from obese donors downregulated ER-α and HER2 expression in breast epithelial cells, providing experimental evidence for pathways linking metabolic dysfunction to receptor-negative tumor development.

Conclusions/Implications:
This study provides convergent evidence that metabolic health is a pivotal, actionable determinant of aggressive breast cancer. The substantial population-attributable risk, supported by direct experimental validation, underscores obesity reduction as a priority for cancer prevention. Integrating metabolic risk reduction into cancer-control and public health strategies has the potential to meaningfully reduce the global burden of TNBC and inform evidence-based prevention policy.