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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

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Estrogen Metabolism Pathways in Pregnancy and Subsequent Breast Cancer Risk: A Prospective Follow-up Study.

Rebecca Troisi¹, Roni Falk¹, Helja-Marja Surcel²

¹National Cancer Institute, National Institutes of Health.

Research Square

|December 3, 2025

Summary

High estrogen levels during pregnancy are linked to increased risk of hormone receptor-negative (HR-) breast cancer. Specific estrogen metabolites, particularly those in the 16-hydroxylation pathway, showed associations with elevated risk in offspring.

Keywords:

estrogen and progesterone receptor negative breast cancer estrogen metabolism maternal hormones pregnancy

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Changes in Mammary Gland Morphology and Breast Cancer Risk in Rats

Changes in Mammary Gland Morphology and Breast Cancer Risk in Rats

Published on: October 16, 2010

Area of Science:

Reproductive Endocrinology
Cancer Epidemiology
Biomarkers of Disease Risk

Background:

Post-pregnancy breast cancer risk, especially for hormone receptor-negative (HR-) tumors, is elevated.
Maternal circulating estrogens during pregnancy's breast remodeling phase are implicated in HR- tumor risk.
The influence of estrogen metabolism during pregnancy on subsequent HR- breast cancer risk remains unclear.

Purpose of the Study:

To investigate the association between maternal serum estrogens and their metabolites during pregnancy and the risk of subsequent invasive, estrogen receptor/progesterone receptor-negative (ER-/PR-) breast cancer.
To explore whether specific estrogen metabolic pathways during pregnancy influence this risk.

Main Methods:

Population-based case-control study using the Finnish Maternity Cohort Biobank and Finnish Cancer Registry.
Serum samples from first and second trimesters of pregnancy analyzed for estrogens and metabolites using LC-MS/MS.
Matched analysis of 449 invasive ER-/PR- breast cancer cases and 449 controls within 20 years of pregnancy.

Main Results:

Total estrogens during pregnancy were positively associated with ER-/PR- breast cancer risk.
Metabolites in the 16-hydroxylation pathway (estriol, 16-epiestriol, 17-epiestriol) showed positive associations with breast cancer risk.
No significant association was found with the ratio of 2:16 hydroxylation pathway metabolites.

Conclusions:

Maternal estrogen concentrations during pregnancy are associated with an increased risk of subsequent ER-/PR- breast cancer.
The specific metabolic pathway of estrogens during pregnancy did not show a consistent pattern of association, suggesting total estrogen levels are key.
Findings highlight the potential role of pregnancy hormonal environment in long-term breast cancer development.