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Obesity is a major modifiable factor associated with ER-negative breast cancer: epidemiological and mechanistic evidence from a high-risk cohort
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Obesity is a major modifiable factor associated with ER-negative breast cancer: epidemiological and mechanistic evidence from a high-risk cohort
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Journal Article
Obesity is a major modifiable factor associated with ER-negative breast cancer: epidemiological and mechanistic evidence from a high-risk cohort
2025
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Age
/ Biomedical and Life Sciences
/ Breast Neoplasms - epidemiology
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Complications and side effects
/ Erb-b2 Receptor Tyrosine Kinases - genetics
/ Erb-b2 Receptor Tyrosine Kinases - metabolism
/ Estrogen Receptor alpha - genetics
/ Estrogen Receptor alpha - metabolism
/ Female
/ Humans
/ Obesity
/ Oncology
/ Parity
/ Triple Negative Breast Neoplasms - epidemiology
/ Triple Negative Breast Neoplasms - metabolism
/ Triple Negative Breast Neoplasms - pathology
