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Early-Life Body Adiposity and the Breast Tumor Transcriptome
Jun Wang1,2, Cheng Peng3, Catherine Guranich4
1Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Journal of the National Cancer Institute
|November 2, 2020
Summary
Early-life adiposity is linked to lower breast cancer risk, but molecular links are unclear. This study found that larger adolescent body size in the Nurses' Health Study was associated with altered gene expression pathways in breast tumors, offering new biological insights.
Area of Science:
- Molecular biology
- Cancer research
- Epidemiology
Background:
- Epidemiologic studies show a strong inverse association between early-life adiposity and lifelong breast cancer risk, independent of adult obesity.
- The molecular mechanisms underlying this association remain largely unknown.
Purpose of the Study:
- To investigate the association between early-life adiposity and the transcriptome of breast tumors and adjacent normal tissue.
- To explore potential molecular pathways involved in the relationship between adolescent body size and breast cancer development.
Main Methods:
- Assessed early-life adiposity using a validated 9-level pictogram for body size during ages 10-20 years in the Nurses' Health Study cohort.
- Analyzed the transcriptome of breast tumors (N=835) and tumor-adjacent normal tissue (N=663) using multivariable linear regression.
- Performed molecular pathway analysis using Hallmark gene sets, stratified by estrogen receptor (ER) status.
Main Results:
- No individual genes showed statistically significant differential expression after multiple comparison adjustment.
- Pathway analysis revealed significant alterations: larger adolescent body size was associated with decreased cellular proliferation (MYC targets) in both ER+ and ER- tumors.
- In ER+ tumors, larger body size correlated with increased TNFα/NFkB signaling. In ER- tumors, it was linked to downregulated interferon signaling and PI3K/AKT/mTOR pathways.
Conclusions:
- Early-life adiposity is associated with specific molecular pathway alterations in breast tumors, providing biological insights into the observed inverse association with breast cancer risk.
- Findings highlight the role of cellular proliferation, inflammatory signaling, and metabolic pathways in mediating the effects of adolescent body size on breast cancer.
