Mediation analysis of the alcohol‐postmenopausal breast cancer relationship by sex hormones in the EPIC cohort
Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testostero...
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| Published in | International journal of cancer Vol. 146; no. 3; pp. 759 - 768 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hoboken, USA
John Wiley & Sons, Inc
01.02.2020
Wiley Subscription Services, Inc Wiley |
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| Online Access | Get full text |
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| Abstract | Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex‐hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol‐consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol‐related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor‐positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1‐standard deviation (1‐SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol‐related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1‐SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol‐BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association.
What's new?
Alcohol consumption is associated with an increased risk of breast cancer (BC). However, the mechanisms underlying this association are not yet fully understood. For example, do sex‐hormone levels play a role? In this study, the authors assessed a number of alcohol‐related hormonal signatures. They found that lower levels of sex‐hormone binding globulin (SHBG), combined with higher levels of sex steroids, mediate a substantial proportion of the observed alcohol‐BC association. It is likely that the mechanism involves the interplay of multiple hormones, rather than the action of individual hormones. |
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| AbstractList | Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex‐hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol‐consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol‐related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor‐positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1‐standard deviation (1‐SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol‐related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1‐SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol‐BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association.Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by Partial Least Square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct (NDE) and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor positive tumours with respectively TE=1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-SD deviation increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE=1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone, was associated with BC risk (OR=1.25 (1.07,1.47)) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex‐hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol‐consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol‐related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor‐positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1‐standard deviation (1‐SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol‐related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1‐SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol‐BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. What's new? Alcohol consumption is associated with an increased risk of breast cancer (BC). However, the mechanisms underlying this association are not yet fully understood. For example, do sex‐hormone levels play a role? In this study, the authors assessed a number of alcohol‐related hormonal signatures. They found that lower levels of sex‐hormone binding globulin (SHBG), combined with higher levels of sex steroids, mediate a substantial proportion of the observed alcohol‐BC association. It is likely that the mechanism involves the interplay of multiple hormones, rather than the action of individual hormones. |
| Author | Chirlaque, María‐Dolores Gurrea, Aurelio Barricarte Ferrari, Pietro Bonet, Catalina Viallon, Vivian Onland‐Moret, Charlotte Sánchez Pérez, María José Dashti, S. Ghazaleh Christakoudi, Sofia Kvaskoff, Marina Fournier, Agnès Gils, Carla H. Cervenka, Iris Bueno de Mesquita, H. Bas Tsilidis, Kostas Karakatsani, Anna Assi, Nada Trichopoulou, Antonia Amiano Etxezarreta, Pilar Overvad, Kim Turzanski‐Fortner, Renée Palli, Domenico Tjønneland, Anne Key, Tim Riboli, Elio Ricceri, Fulvio Tumino, Rosario Merino, Susana Grioni, Sara Dossus, Laure Bergmann, Manuela Rinaldi, Sabina Martimianaki, Georgia Boeing, Heiner Ellingjord‐Dale, Merete Kaaks, Rudolf Panico, Salvatore Gunter, Marc J |
| AuthorAffiliation | 8 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy 30 The Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark 15 Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria, IBS GRANADA, Universidad de Granada. Granada, Spain 36 Nutritional Epidemiology Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France 22 Public Health Directorate, Asturias, Spain 27 Julius Center for Health Sciences and Primary Care, Cancer Epidemiology University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands 10 Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco (TO), Italy 20 Navarra Institute for Health Research (IdiSNA) Pamplona, Spain 5 Gustave Roussy, F-94805, Villejuif, France 11 Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy 7 Department of Epidemiology, German Inst |
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| Keywords | alcohol sex steroids breast cancer mediation analysis EPIC hormonal signature |
| Language | English |
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| SubjectTerms | 17β-Estradiol Aged alcohol Alcohol Drinking - adverse effects Alcohol Drinking - blood Alcohol Drinking - epidemiology Alcohol use Breast cancer Breast Neoplasms - epidemiology Breast Neoplasms - etiology Cancer Case-Control Studies EPIC Estradiol - blood Female Globulins hormonal signature Hormone replacement therapy Humans Incidence Life Sciences Mediation mediation analysis Medical research Middle Aged Post-menopause Postmenopause - blood Prospective Studies Sex Hormone-Binding Globulin - analysis Sex hormones sex steroids Statistical analysis Steroid hormones Testosterone Testosterone - blood Tumors |
| Title | Mediation analysis of the alcohol‐postmenopausal breast cancer relationship by sex hormones in the EPIC cohort |
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