Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Breast Cancer Res. 2022 Oct 8;24(1):66. doi: 10.1186/s13058-022-01553-9.

Abstract

Background: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.

Methods: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.

Results: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.

Conclusions: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

Keywords: Breast cancer; Mendelian randomization; Sex steroid hormones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-alpha-Hydroxyprogesterone
  • Adult
  • Aldosterone
  • Androstenedione
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / genetics
  • Dehydroepiandrosterone Sulfate
  • Estradiol
  • Female
  • Genome-Wide Association Study
  • Gonadal Steroid Hormones
  • Humans
  • Hydrocortisone
  • Longitudinal Studies
  • Mendelian Randomization Analysis
  • Progesterone
  • Sex Hormone-Binding Globulin*
  • Testosterone

Substances

  • Gonadal Steroid Hormones
  • Sex Hormone-Binding Globulin
  • Testosterone
  • Androstenedione
  • Aldosterone
  • Progesterone
  • Estradiol
  • Dehydroepiandrosterone Sulfate
  • 17-alpha-Hydroxyprogesterone
  • Hydrocortisone