RESUMO
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. PREVENTION RELEVANCE: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Mama/metabolismo , Relógios Circadianos/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Adulto , Biomarcadores Tumorais/genética , Mama/patologia , Neoplasias da Mama/patologia , Transformação Celular Neoplásica , Células Cultivadas , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Detecção Precoce de Câncer/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Pessoa de Meia-Idade , Especificidade de Órgãos/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismoRESUMO
Alternative RNA splicing is a key step in gene expression that allows generation of numerous messenger RNA transcripts encoding proteins of varied functions from the same gene. It is thus a rich source of proteomic and functional diversity. Alterations in alternative RNA splicing are observed both during healthy aging and in a number of human diseases, several of which display premature aging phenotypes or increased incidence with age. Age-associated splicing alterations include differential splicing of genes associated with hallmarks of aging, as well as changes in the levels of core spliceosomal genes and regulatory splicing factors. Here, we review the current known links between alternative RNA splicing, its regulators, healthy biological aging, and diseases associated with aging or aging-like phenotypes. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.