Obesity and menopause modify the epigenomic profile of breast cancer

Ana B. Crujeiras, Angel Diaz-Lagares, Olafur A. Stefansson, Manuel Macias-Gonzalez, Juan Sandoval, Juan Cueva, Rafael Lopez-Lopez, Sebastian Moran, Jon G. Jonasson, Laufey Tryggvadottir, Elinborg Olafsdottir, Francisco J. Tinahones, Marcos C. Carreira, Felipe F. Casanueva, Manel Esteller

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Obesity is a high risk factor for breast cancer. This relationship could be marked by a specific methylome. The current work was aimed to explore the impact of obesity and menopausal status on variation in breast cancer methylomes. Data from Infinium 450K array-based methylomes of 64 breast tumors were coupled with information on BMI and menopausal status. Additionally, DNA methylation results were validated in 18 non-tumor and 81 tumor breast samples. Breast tumors arising in either pre- or postmenopausal women stratified by BMI or menopausal status alone were not associated with a specific DNA methylation pattern. Intriguingly, the DNA methylation pattern identified in association with the high-risk group (postmenopausal women with high BMI (>25) and premenopausal women with normal or low BMI < 25) exclusively characterized by hypermethylation of 1287 CpG sites as compared with the low-risk group. These CpG sites included the promoter region of fourteen protein-coding genes of which CpG methylation over the ZNF577 promoter region represents the top scoring associated event. In an independent cohort, the ZNF577 promoter methylation remained statistically significant in association with the high-risk group. Additionally, the impact of ZNF577 promoter methylation on mRNA expression levels was demonstrated in breast cancer cell lines after treatment with a demethylating agent (5-azacytidine). In conclusion, the epigenome of breast tumors is affected by a complex interaction between BMI and menopausal status. The ZNF577 methylation quantification is clearly relevant for the development of novel biomarkers of precision therapy in breast cancer.

Original languageEnglish
Pages (from-to)351-363
Number of pages13
JournalEndocrine-Related Cancer
Volume24
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Bibliographical note

Publisher Copyright:
© 2017 Society for Endocrinology.

Other keywords

  • 450k methylation array
  • breast cancer
  • DNA methylation
  • epigenomics
  • obesity

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