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Updated: May 7, 2026
Changes in Mammary Gland Morphology and Breast Cancer Risk in Rats
Published on: October 16, 2010
Plasma C-peptide, mammographic breast density, and risk of invasive breast cancer
Thomas P Ahern1, Susan E Hankinson, Walter C Willett
1Authors' Affiliations: Channing Division of Network Medicine, Brigham and Women's Hospital & Harvard Medical School; Department of Epidemiology; Department of Nutrition, Harvard School of Public Health, Boston; Division of Biostatistics and Epidemiology, University of Massachusetts School of Public Health and Health Sciences, Amherst, Massachusetts; and Department of Medicine, McGill University, Montréal, Quebec, Canada.
Background:
Insulin may promote breast cancer directly by stimulating the insulin receptor or indirectly by increasing the plasma concentration of active sex hormones. The association between insulin and breast density, a strong breast cancer risk factor, has not been thoroughly studied. We measured associations between c-peptide (a molar marker of insulin secretion), breast cancer risk, and breast density measurements in case-control studies nested within the Nurses' Health Study and Nurses' Health Study II cohorts.
Methods:
Breast cancer associations were estimated with multivariate logistic regression models and then pooled across cohorts (total n = 1,084 cases and 1,785 controls). Mammographic density associations (percent dense area, dense area, and nondense area) were estimated as the difference in least-square means of the density parameters between quartiles of c-peptide concentration in all breast cancer controls with available screening mammography films (n = 1,469).
Results:
After adjustment for adiposity, c-peptide was not associated with any measure of breast density. However, c-peptide was associated with an approximately 50% increased risk of invasive breast cancer [top vs. bottom quartile, adjusted OR = 1.5, 95% confidence interval (CI), 1.1-2.0] that was robust to adjustment for plasma-free estradiol and sex hormone-binding globulin. The association was stronger for ER-negative disease (adjusted OR = 2.0; 95% CI, 1.2-3.6).
Conclusions:
Our data suggest a positive association between hyperinsulinemia and breast cancer risk that occurs through nonestrogenic mechanisms, and that is not mediated by breast density.
Impact:
Primary prevention of breast cancer in women with hyperinsulinemia may be possible by targeting insulin signaling pathways.
