ArticleCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology2025
Circulating Estrogen Metabolites and Risk of Breast Cancer among Postmenopausal Women in the Nurses' Health Study.
Article in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Plasma metabolites, dietary intakes, and breast cancer incidence: a prospective case-cohort study in NutriNet-Santé.The American journal of clinical nutrition · 2026Article
- Estrogen metabolism-related lifestyle score and risk of postmenopausal breast, endometrial, and ovarian cancers: findings from two large prospective cohort studies.Cancer prevention research (Philadelphia, Pa.) · 2026Article
- Genistein Reduces Anxiety-like Behavior During Metestrus-Diestrus Phase Without Changing Estradiol or Progesterone Levels in Wistar Rats.Metabolites · 2025Article
- Retina-Targeted 17β-Estradiol by the DHED Prodrug Rescues Visual Function and Actuates Neuroprotective Protein Networks After Optic Nerve Crush in a Rat Model of Surgical Menopause.International journal of molecular sciences · 2025Article
- Estrogens and breast cancer.Annals of oncology : official journal of the European Society for Medical Oncology · 2025Review
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Abstract
backgroundEstradiol and estrone are well-established risk factors for postmenopausal breast cancer. Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at position 2 or 16, may independently influence carcinogenesis.
methodsWe performed a nested case-control study of breast cancer (328 breast cancer cases; 639 controls) among postmenopausal women within the Nurses' Health Study to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated + conjugated forms) were measured by LC-MS/MS. Multivariable conditional logistic regression, adjusting for breast cancer risk factors, estimated relative risks (RR) and 95% confidence intervals of breast cancer across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen receptor (ER) and progesterone receptor (PR) status were analyzed by unconditional logistic regression.
resultsEstradiol and estrone were strongly associated with increased breast cancer risk [estradiol: RRQ5 vs. Q1 (95% confidence interval) = 2.64 (1.64-4.26); estrone: 2.78 (1.74-4.45); both P-trends <0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5 vs. Q1 = 3.09 (1.81-5.27); P-trend <0.001] and remained so after adjusting for unconjugated estradiol [RRQ5 vs. Q1 = 2.23 (1.25-3.96); P-trend = 0.01]. Although the 16-hydroxylation pathway was modestly associated with risk [RRQ5 vs. Q1 = 1.62 (1.03-2.54); P-trend = 0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5 vs. Q1 = 1.24 (0.77-1.99); P-trend = 0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER-/PR- tumors.
conclusionsIn this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased breast cancer risk, independent of unconjugated estradiol. IMPACT: These results highlight the need to revisit the role of estrogen metabolism in breast cancer etiology and prevention. See related In the Spotlight, p. 367.
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