Devon J Boyne1,2, Christine M Friedenreich1,2,3, John B McIntyre4, Frank Z Stanczyk5, Kerry S Courneya6, Will D King7. 1. Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Holy Cross Centre, 2210-2nd Street SW, Box ACB, Calgary, AB, T2S 3C3, Canada. 2. Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, TRW Building, 3rd Floor, 3280 Hospital Drive NW, Calgary, T2N 4Z6, AB, Canada. 3. Department of Oncology, Cumming School of Medicine, University of Calgary, 1331 29th Street NW, Calgary, T2N 4N2, AB, Canada. 4. Translational Laboratory, Tom Baker Cancer Centre, Department of Oncology, University of Calgary, Room AGE 90, 1331 29th Street NW, Calgary, AB, T2N 4N2, Canada. 5. Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California Keck School of Medicine, LRB 201, Off Campus, Los Angeles, CA, 90089-9250, USA. 6. Faculty of Physical Education and Recreation, University of Alberta, 1-113 University Hall, Edmonton, AB, T6G 2H9, Canada. 7. Department of Public Health Sciences, Queen's University, Carruthers Hall, 62 Fifth Field Company Lane, 2nd floor, Kingston, ON, K7L 3N6, Canada. kingw@queensu.ca.
Abstract
PURPOSE: Epigenetic mechanisms may help to explain the complex and heterogeneous relation between sex hormones and cancer. Few studies have investigated the effects of sex hormones on epigenetic markers related to cancer risk such as levels of methylation within repetitive DNA elements. Our objective was to describe the association between endogenous sex hormone exposure and levels of LINE-1 and Alu methylation in healthy postmenopausal women. METHODS: We nested a cross-sectional study within the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2006). Study participants consisted of healthy postmenopausal women who had never been diagnosed with cancer (n = 289). Sex hormone exposures included serum concentrations of estradiol, estrone, testosterone, androstenedione, and sex hormone-binding globulin. We estimated the participants' lifetime number of menstrual cycles (LNMC) as a proxy for cumulative exposure to ovarian sex hormones. Buffy coat samples were assessed for DNA methylation. Linear regression was used to model the associations of interest and to control for confounding. RESULTS: Both estradiol and estrone had a significant positive dose-response association with LINE-1 methylation. LNMC was associated with both LINE-1 and Alu methylation. Specifically, LNMC had a non-linear "U-shaped" association with LINE-1 methylation regardless of folate intake and a negative linear association with Alu methylation, but only amongst low folate consumers. Androgen exposure was not associated with either outcome. CONCLUSION: Current and cumulative estrogen exposure was associated with repetitive element DNA methylation in a group of healthy postmenopausal women. LINE-1 and Alu methylation may be epigenetic mechanisms through which estrogen exposure impacts cancer risk.
PURPOSE: Epigenetic mechanisms may help to explain the complex and heterogeneous relation between sex hormones and cancer. Few studies have investigated the effects of sex hormones on epigenetic markers related to cancer risk such as levels of methylation within repetitive DNA elements. Our objective was to describe the association between endogenous sex hormone exposure and levels of LINE-1 and Alu methylation in healthy postmenopausal women. METHODS: We nested a cross-sectional study within the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2006). Study participants consisted of healthy postmenopausal women who had never been diagnosed with cancer (n = 289). Sex hormone exposures included serum concentrations of estradiol, estrone, testosterone, androstenedione, and sex hormone-binding globulin. We estimated the participants' lifetime number of menstrual cycles (LNMC) as a proxy for cumulative exposure to ovarian sex hormones. Buffy coat samples were assessed for DNA methylation. Linear regression was used to model the associations of interest and to control for confounding. RESULTS: Both estradiol and estrone had a significant positive dose-response association with LINE-1 methylation. LNMC was associated with both LINE-1 and Alu methylation. Specifically, LNMC had a non-linear "U-shaped" association with LINE-1 methylation regardless of folate intake and a negative linear association with Alu methylation, but only amongst low folate consumers. Androgen exposure was not associated with either outcome. CONCLUSION: Current and cumulative estrogen exposure was associated with repetitive element DNA methylation in a group of healthy postmenopausal women. LINE-1 and Alu methylation may be epigenetic mechanisms through which estrogen exposure impacts cancer risk.
Entities:
Keywords:
DNA methylation; Epigenetics; Estrogen; Repetitive elements; Sex hormones
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