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AS321 - Gentoxic Estrogen Ratio: A Novel Estrogen Biomarker and Breast Cancer Risk

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Kerryn Reding [kreding@uw.edu]

Introduction/Intent

A large accumulation of data has implicated estrogen in breast cancer (BC) development.  The catechol estrogen (CE) pathway has been a focus of BC research because particular CE metabolites are capable of forming DNA adducts. Recently, Cavalieri and colleagues developed an assay to identify estrogen DNA adducts (EDA) in urine. They observed in 75 women that a ratio of EDA to their unbound counterparts (estrogen metabolites and conjugates [EMC]) was higher in BC patients and healthy women at high risk of BC compared to low-risk, healthy controls. While this study supports the hypothesis that BC development is influenced by CE-DNA adducts, these data require replication in a large, prospective study. We propose to use urine samples from 352 BC cases and 704 controls from the WHI observational study and control arm of the dietary modification trial for a nested case-control study investigating whether the EDA:EMC ratio is associated with  BC risk (Specific Aim 1) and examine whether hormone-related BC risk factors are associated with the EDA:EMC ratio (Specific Aim 2). The proposed study would be the first prospective study of BC risk in relation to this novel, estrogen biomarker.  Data emanating from this proposal could elucidate hormonal mechanisms involved in BC development.

Materials/Methods

Two small-scale studies have reported that women at increased risk of breast cancer (BC) have elevated levels of genotoxic metabolites within the catechol estrogen (CE) pathway.^{1, 2}  These particular estrogen biomarkers may play a role in BC initiation due to their ability to form mutations within the DNA.^1-4 Specifically, this biomarker consists of estrogen-DNA adduct (EDA) compounds which are excreted in the urine and may be an indicator of the level of the catechol estrogen's genotoxicity within an individual.^{1, 2}  Recently, the Cavalieri laboratory demonstrated that a ratio of EDA to their unbound counterparts (estrogen metabolite and conjugates [EMC]) can serve as a biologic marker of the level of DNA adduct formation resulting from hydroxy estrogen quinones.  They also demonstrated that BC cases and high-risk women (defined by their Gail score³) had significantly higher EDA:EMC ratios than low-risk, healthy women in a sample of 75 women;² the authors replicated these findings in a second, small-scale study.¹  However, large prospective studies investigating potential associations between the EDA:EMC ratio and BC have not been conducted.  In collaboration with Cavalieri and colleagues, we propose to investigate associations between the EDA:EMC ratio and BC risk, as well as investigate whether the EDA:EMC ratio is associated with hormonal risk factors, using a nested case-control study within the Women's Health Initiative (WHI) observational study (OS) and control arm of the WHI Dietary Modification(DM) Randomized Control Trial (RCT).

We propose to test the following Specific Aims:

1. To estimate the risk of breast cancer in relation to the EDA:EMC ratio in prospectively collected urine samples.  We hypothesize that BC risk will be elevated in women with higher EDA:EMC ratios.
1. To examine the association between the EDA:EMC ratio and ER+ breast cancer.  Because estrogen receptors are thought to facilitate the entry of catechol estrogens into the nucleus of the cell, we hypothesize that the association of the EDA:EMC ratio with ER+ breast cancer may be stronger than with breast cancer overall.  
2. To investigate whether hormone-related risk factors for BC are associated with the EDA:EMC ratio.  We hypothesize that hormone-related risk factors (e.g. use of estrogen-progestin therapy [EPT]) are positively associated with the EDA:EMC ratio.
   
   Based on the findings of the earlier studies of EDA:EMC ratio in relation to BC,^{1, 2} these biomarkers warrant follow-up in a large, prospective epidemiologic study. To our knowledge, no such study has been conducted or proposed.  The data most needed to move this line of research forward is an estimate of BC risk in relation to high EDA:EMC ratios.  The WHI OS and DM-RCT, which collected urine prospectively in postmenopausal women, represents a valuable resource for addressing this important research question.  Findings from this research could elucidate biological mechanisms related to hormonal initiation of cancer and contribute data on the utility of this novel, estrogen biomarker which could be utilized in future studies of breast cancer.

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Results/ Findings

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