Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women.
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ABSTRACT:
SUBMITTER: Sampson JN
PROVIDER: S-EPMC5313342 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women.
Sampson Joshua N JN Falk Roni T RT Schairer Catherine C Moore Steven C SC Fuhrman Barbara J BJ Dallal Cher M CM Bauer Douglas C DC Dorgan Joanne F JF Shu Xiao-Ou XO Zheng Wei W Brinton Louise A LA Gail Mitchell H MH Ziegler Regina G RG Xu Xia X Hoover Robert N RN Gierach Gretchen L GL
Cancer research 20161223 4
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohor ...[more]
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Project description:BackgroundEstrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites.MethodsWe conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided.ResultsNearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol.ConclusionsMore extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.
| S-EPMC3283536 | biostudies-literature
Project description:Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography-tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1 = 1.86; 95% CI: 1.19-2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1 = 0.69; 95% CI: 0.46-1.05; P trend = 0.01) and 4-hydroxylation pathway (HRQ5vsQ1 = 0.61; 95% CI: 0.40-0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1 = 0.60; 95% CI: 0.40-0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.
| S-EPMC3908751 | biostudies-literature
Project description:It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16?-hydroxylation pathway may be inversely associated with breast cancer risk.We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone (2-OHE1), 16?-hydroxyestrone (16?-OHE1), and the 2-OHE1:16?-OHE1 ratio in a case-control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16?-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation.Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16?-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (P ? 0.03). We observed a protective association of 2-OHE1 with ER+ breast cancer [multivariate-adjusted OR for a doubling of 2-OHE1, 0.67 (95% confidence interval [CI], 0.48-0.94; P = 0.02)].In this study, higher levels of 2-OHE1 were associated with reduced risk of ER+ breast cancer in postmenopausal women after adjustment for circulating estrone.These results suggest that taking into account the levels of parent estrogens and ER status is important in studies of estrogen metabolites and breast cancer.
| S-EPMC4082442 | biostudies-literature
Project description:The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.
| S-EPMC5858156 | biostudies-literature
Project description:Increased exposure to estrogen is a risk factor for postmenopausal breast cancer, and dietary factors can influence estrogen metabolism. However, studies of diet and breast cancer have been inconclusive. We developed a dietary pattern associated with levels of unconjugated estradiol and the ratio of 2- and 16-hydroxylated estrogen metabolites in a subsample of Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) participants (n = 653) using reduced rank regression, and examined its association with postmenopausal breast cancer prospectively in the larger PLCO cohort (n = 27,488). The estrogen-related dietary pattern (ERDP) was comprised of foods with positively-weighted intakes (non-whole/refined grains, tomatoes, cruciferous vegetables, cheese, fish/shellfish high in ω-3 fatty acids, franks/luncheon meats) and negatively-weighted intakes (nuts/seeds, other vegetables, fish/shellfish low in ω-3 fatty acids, yogurt, coffee). A 1-unit increase in the ERDP score was associated with an increase in total (HR: 1.09, 95% CI: 1.01-1.18), invasive (HR: 1.13; 95% CI: 1.04-1.24) and estrogen receptor (ER)-positive (HR: 1.13, 95% CI: 1.02-1.24) breast cancer risk after adjustment for confounders. Associations were observed for the fourth quartile of ERDP compared with the first quartile for overall breast cancer (HR: 1.14; 95% CI: 0.98-1.32), invasive cases (HR: 1.20, 95% CI: 1.02-1.42) and ER-positive cases (HR: 1.19; 95% CI: 0.99-1.41). The increased risk associated with increasing ERDP score was more apparent in strata of some effect modifiers (postmenopausal hormone therapy non-users and non-obese participants) where the relative estrogen exposure due to that factor was lowest, although the p values for interaction were not statistically significant. Results suggest a dietary pattern based on estrogen metabolism is positively associated with postmenopausal breast cancer risk, possibly through an estrogenic influence.
| S-EPMC6019153 | biostudies-literature
Project description:ImportanceThe role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties.ObjectiveTo evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk.Design, setting, and participantsUsing a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018.ExposuresCirculating concentrations of pregnenolone, progesterone, and their major metabolites.Main outcomes and measuresDevelopment of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori.ResultsThe present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction).Conclusions and relevanceIn this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.
| S-EPMC7182797 | biostudies-literature
Project description:Breast cancer is a hormonally-driven cancer, and various dietary factors are associated with estrogen metabolism, including dietary fiber. Several studies report associations between dietary fiber and breast cancer; however, research on whether fiber influences circulating estrogens through the gut microbiota is rare. The objective of this cross-sectional study among 29 newly-diagnosed (stage 0-II), post-menopausal breast cancer patients is to examine associations between dietary fiber and the gut microbiota that are linked with β-glucuronidase activity, and purportedly increase circulating estrogens. Spearman's and partial correlations controlling for body mass index and age were performed using dietary recall data, Illumina MiSeq generated microbiota relative abundance, and HPLC-mass spectrometry-derived estradiol and estrone levels.Major findings are: (1) total dietary fiber is inversely associated with Clostridium hathewayi (r= -0.419; p = 0.024); (2) soluble fiber is inversely associated with Clostridium (r=-0.11; p = 0.02); (3) insoluble fiber is positively associated with Bacteroides uniformis sp. (r = 0.382; p = 0.041); and (4) serum estradiol and estrone levels are not correlated with species/genera or dietary fiber, though there is a trend toward an inverse association between soluble fiber and estradiol levels (r= -0.30; p = 0.12). More studies are needed to understand the complex interaction between dietary fiber, intestinal microbiota, and hormonal levels in older females.
| S-EPMC7875566 | biostudies-literature
Project description:BACKGROUND: The estrogen receptor alpha (ESR1) is a mediator of estrogen response in the breast. The most studied variants in this gene are the PvuII and XbaI polymorphisms, which have been associated to lower sensitivity to estrogen. We evaluated whether these polymorphisms were associated with breast cancer risk by means of an association study in a population of Caucasian postmenopausal women from the Rotterdam study and a meta-analysis of published data. METHODS: The PvuII and XbaI polymorphisms were genotyped in 3,893 women participants of the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted logistic regression analyses to assess the risk of breast cancer by each of the ESR1 genotypes. Meta-analyses of all publications on these relations were done by retrieving literature from Pubmed and by further checking the reference lists of the articles obtained. RESULTS: There were 38 women with previously diagnosed breast cancer. During follow-up, 152 were additionally diagnosed. The logistic regression analyses showed no difference in risk for postmenopausal breast cancer in carriers of the PvuII or XbaI genotypes neither in overall, incident or prevalent cases. No further evidence of a role of these variants was found in the meta-analysis. CONCLUSIONS: Our results suggest that the ESR1 polymorphisms do not play a role in breast cancer risk in Caucasian postmenopausal women.
| S-EPMC2217623 | biostudies-other
Project description:ContextIn the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.ObjectiveTo determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.Design, setting, and participantsA total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.Main outcome measuresInvasive breast cancer incidence and breast cancer mortality.ResultsIn intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.ConclusionsEstrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.Trial registrationclinicaltrials.gov Identifier: NCT00000611.
| S-EPMC5142300 | biostudies-literature
Project description:BACKGROUND:Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites. METHODS:We conducted a nested case-control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk. RESULTS:Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95-13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m(2), BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01). CONCLUSIONS:Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens. IMPACT:These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081-9. ©2016 AACR.
| S-EPMC4930692 | biostudies-literature