Epidemiologic studies of estrogen metabolism and breast cancer

Abstract

Early epidemiologic studies of estrogen metabolism measured only 2-hydroxyestrone and 16α-hydroxyestrone and relied on direct enzyme immunoassays without purification steps. Eight breast cancer studies have used these assays with prospectively collected blood or urine samples. Results were inconsistent, and generally not statistically significant; but the assays had limited specificity, especially at the low concentrations characteristic of postmenopausal women. To facilitate continued testing in population-based studies of the multiple laboratory-based hypotheses about the roles of estrogen metabolites, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to measure concurrently all 15 estrogens and estrogen metabolites in human serum and urine, as unconjugated and total (glucuronidated+sulfated+unconjugated) concentrations. The assay has high sensitivity (lower limit of quantitation ~1–2 pmol/L), reproducibility (coefficients of variation generally ≤5%), and accuracy. Three prospective studies utilizing this comprehensive assay have demonstrated that enhanced 2-hydroxylation of parent estrogens (estrone+estradiol) is associated with reduced risk of postmenopausal breast cancer. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort, the serum ratio of 2-hydroxylation pathway metabolites to parent estrogens was associated with a 28% reduction in breast cancer risk across extreme deciles (p-trend=.05), after adjusting for unconjugated estradiol and breast cancer risk factors. Incorporating this ratio into a risk prediction model already including unconjugated estradiol improved absolute risk estimates substantially (by ≥14%) in 36% of the women, an encouraging result that needs replication. Additional epidemiologic studies of the role of estrogen metabolism in the etiology of hormone-related diseases and continued improvement of estrogen metabolism assays are justified.

Serum Estrogens and Estrogen Metabolites and Endometrial Cancer Risk among Postmenopausal Women

“…The use of mass spectrometry to measure endogenous hormones has opened up new research avenues (7). In addition to improving sensitivity, accuracy and reproducibililty, these assays have enabled concurrent measurement of estrogen metabolites, which purportedly have divergent effects on cancer development.…”

“…The metabolism of estradiol or estrone with irreversible hydroxylation at the C-2, -4, or -16 positions of the steroid ring results in metabolites with varying mitogenic and genotoxic properties. Two major hypotheses about estrogen metabolites have emerged from experimental research, namely that 1) 16α-hydroxyestrone is carcinogenic because it can bind covalently to the estrogen receptor with strong mitogenic effects, and 2) the 2- and 4-hydroxylation catechol estrogen metabolites are carcinogenic because they can be oxidized into mutagenic quinones that form DNA adducts and lead to oxidative DNA damage (7). …”

Sleep and circadian disruption and incident breast cancer risk: An evidence-based and theoretical review

“…Melatonin is also a potent repressor of estrogen-induced estrogen-receptor-α (ERα) transcriptional activity (Ram et al, 2002), an action that is attenuated by LAN exposure. Elevated levels of ovarian hormones contribute to the development of breast cancers (e.g., (Shafie and Grantham, 1981; Ziegler et al, 2015), and high levels of endogenous estrogen are associated with increased risk of incident breast cancer in both pre- and post-menopausal women (Key et al, 2013), respectively). These findings highlight the importance of an estrogen-suppressing mechanism such as melatonin in a model of breast cancer pathogenesis.…”

Ultra-high sensitivity analysis of estrogens for special populations in serum and plasma by liquid chromatography–mass spectrometry: Assay considerations and suggested practices

“…Estrogens are thought to act through either estrogen receptor (ER)-dependent or ER-independent mechanisms [21, 22]. The mechanism mediated by ER results in direct stimulation of aberrant cell proliferation, a factor causally related to breast cancer development [23, 24].…”

“…Circulating androgens can also serve as estrogen precursors in postmenopausal women (through the action of aromatase), which provides a fundamentally different source of estrogens when compared to the contributors to estrogen metabolites in premenopausal women [6, 31, 38]. Thus, considering their effects and metabolism, estrogens as well as their metabolites in the circulation are valuable biomarkers of tissue estrogen biosynthesis and metabolism [22, 39, 40]. …”