The ELF5 clock: A predictive marker for accelerated breast tissue aging and cancer susceptibility

Aging is the most significant risk factor for breast cancer (BC). It is associated with transformative changes, notably a striking loss of lineage fidelity in luminal epithelial cells. This loss is characterized by a decline in lineage-specific gene expression and the acquisition of EMT- and myoepithelial-like features, along with increased transcriptional and methylome variability. In young women harboring pathogenic mutations in BRCA1, BRCA2, and PALB2, these aging-associated phenotypes, including loss of lineage fidelity in luminal epithelial cells, are accelerated. These changes warrant closer examination as luminal epithelial cells are the likely cells of origin for the BC subtypes most associated with aging. We hypothesize that the loss of lineage fidelity is a critical factor underlying the increased susceptibility to malignant transformation in mammary epithelia. A key age-related alteration in luminal cells is the decreased expression of the transcription factor ELF5. ELF5 is crucial for mammary gland development, maintaining the ER- luminal epithelial cell state, and its dysregulation is observed in BCs. Changes in ELF5 expression and promoter-proximal methylation serve as a biological clock for breast tissue. The expression of ELF5 decreases in luminal cells in an approximately linear fashion with chronological age, driven by changes in regulatory binding factors and promoter-proximal DNA methylation. The age-associated reduction in ELF5 expression, mirrored by alterations in its target genes, suggests that a decline in ELF5 may be a pivotal event leading to the loss of lineage fidelity. We demonstrate that the ELF5 clock predicts breast biological age within ±3 years of chronological age in women at average risk. High-risk carriers of BRCA1, BRCA2, or PALB2 variants, exhibit a biological age acceleration of 10-40 years relative to their chronological age. We hypothesize that ELF5 expression levels in luminal cells reflect the susceptibility of breast tissue to cancer, independent of specific environmental, epigenetic, genetic, or age-related factors contributing to increased risk. We propose that measuring ELF5 could serve as a molecular “canary in the coal mine” for BC risk or as a clinical correlate for monitoring preventive interventions.