Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort

Nada Assi, Sabina Rinaldi, Vivian Viallon, S. Ghazaleh Dashti, Laure Dossus, Agnès Fournier, Iris Cervenka, Marina Kvaskoff, Renée Turzanski-Fortner, Manuela Bergmann, Heiner Boeing, Salvatore Panico, Fulvio Ricceri, Domenico Palli, Rosario Tumino, Sara Grioni, María José Sánchez Pérez, María Dolores Chirlaque, Catalina Bonet, Aurelio Barricarte GurreaPilar Amiano Etxezarreta, Susana Merino, H. Bas Bueno de Mesquita, Carla H. van Gils, Charlotte Onland-Moret, Anne Tjønneland, Kim Overvad, Antonia Trichopoulou, Georgia Martimianaki, Anna Karakatsani, Tim Key, Sofia Christakoudi, Merete Ellingjord-Dale, Kostas Tsilidis, Elio Riboli, Rudolf Kaaks, Marc J. Gunter, Pietro Ferrari*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)759-768
Number of pages10
JournalInternational Journal of Cancer
Issue number3
Early online date10 Apr 2019
Publication statusPublished - 1 Feb 2020


  • alcohol
  • breast cancer
  • EPIC
  • hormonal signature
  • mediation analysis
  • sex steroids


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