Breast-Specific Molecular Clocks Comprised ofELF5Expression and Promoter Methylation Identify Individuals Susceptible to Cancer Initiation
Abstract
A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5, a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5-proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 17, 2021
- Source ID
- 10.1158/1940-6207.capr-20-0635
Entities
People
- Arrianna Zirbes
- Brittany Angarola
- Jennifer C. Lopez
- Lisa D Yee
- Mark A LaBarge
- Martha R Stampfer
- Masaru Miyano
- Mina Sedrak
- Olga Anczuków
- Parijat Senapati
- Rosalyn W. Sayaman
- Stefan Hinz
- Sundus Shalabi
- Victoria L. Seewaldt
Organizations
- City of Hope National Medical Center
- Conrad N. Hilton Foundation
- Lawrence Berkeley National Laboratory
- National Cancer Institute
- National Institute of Biomedical Imaging and Bioengineering
- National Institutes of Health
- University of Bergen
- University of California, San Francisco