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Principal Investigator
Regina Ziegler
Position Title
About this CDAS Project
PLCO (Learn more about this study)
Project ID
Initial CDAS Request Approval
Aug 29, 2008
Estrogens and Estrogen Metabolites (EMs) and the Risk of Endometrial Cancer in a Nested Case-Control Study in the Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial (PLCO)
Established risk factors for endometrial cancer are commonly attributed to a single underlying etiologic pathway: exposure of endometrial tissues to relatively high levels of estrogens unopposed by progestins. While estrogens are commonly recognized as playing a role in both breast and endometrial carcinogenesis, the mechanisms of estrogen-mediated carcinogenesis remain controversial, may involve multiple pathways, and may be tissue-specific. Estrogens are metabolized at both systemic and target tissue levels, and resulting metabolites vary with respect to their affinities to estrogen receptors, their availability to target tissues, and their susceptibility to oxidative conversion into reactive species. While large interindividual differences in estrogen metabolism have been observed, little is known about the physiological and pathologic importance of this natural variability. We have developed a sensitive, accurate, and precise technique for simultaneous measurement of 15 estrogens and estrogen metabolites (EMs), which will allow us to test hypotheses regarding the role of total estrogen exposure, patterns of estrogen metabolism, and particular EMs in the pathogenesis of this disease. We are proposing a nested case-control study in the PLCO screening arm to compare circulating levels of free and total (conjugated + free) EMs in prospectively stored sera for participants with incident primary endometrial cancer and matched controls.

The overall goal of the proposed research is to evaluate the role of total estrogen exposure, circulating levels of conjugated and free estrogens and estrogen metabolites (EMs), and individual patterns of estrogen metabolism in the etiology of endometrial cancer (EC). In a nested case-control study, we will measure circulating levels of 15 individual EMs in prospectively stored sera collected at baseline from participants randomized to the PLCO screening arm and assess associations with subsequent incidence of EC. Our method will assay both free (unconjugated) and total (sulfated, glucuronidated, and free) forms of each EM. We will use a liquid chromatography-tandem mass spectrometry (LC/MS2) method that several of us have recently developed, which allows a view of circulating estrogen profiles that is unprecedented in its accuracy, precision, sensitivity, and breadth. 1. To determine risk of EC by circulating levels of each EM and all EMs combined, for both free and total EM. 2. To determine which measure of estrogen exposure is the best predictor of EC risk. 3. To test hypotheses regarding specific estrogen metabolic pathways that may modulate risk of EC. A. Free EMs are more strongly associated with risk of EC than conjugated EMs. B. Estrogenicity [estrogen receptor (ER) affinity and selectivity] of EM profiles account for variability in risk of endometrial cancer. C. Relative activity of competing hydroxylation pathways (2-, 4-, and 16a- hydroxylation) accounts for variability in risk of EC. D. Methylation of the hydroxyl group of reactive catechol estrogens reduces risk of EC. 4. To look at the associations of individual EMs and EM patterns with EC risk in subgroups defined by HRT use and EC subtypes. 5. To test for associations of circulating EM levels and EM patterns with age, menstrual history, reproductive history, obesity, HRT use, alcohol use). 6. To assess whether selected measures of estrogen exposure and estrogen metabolism are better predictors of EC risk than obesity and HRT use.


Barbara Fuhrman (NCI, DCEG)
Mitchell Gail (NCI, DCEG)
Robert Hoover (NCI, DCEG)
Larry Keefer (NCI/DBS/LCC)
James Lacey (NCI, DCEG)
Ruth Pfeiffer (NCI, DCEG)
Tim Veenstra (SAIC, Inc.)
Jocelyn Weiss (NCI, DCEG)
Xia Xu (SAIC, Inc.)
Regina Ziegler (None specified)