Evaluating the ELF5 Clock as a Biomarker in Breast Cancer Prevention Trials - Breast cancer is the most prevalent cancer among women in the United States, with projections indicating a substantial increase in newly diagnosed cases by 2040, largely due to the aging population. Prevention emerges as a viable strategy to curb this rise. A major challenge in breast cancer prevention clinical trial design is a dearth of biomarkers predictive of risk reduction. Indeed, there is an urgent need to develop biomarkers capable of detecting the biological effects of interventions, facilitating a more accurate assessment of their effectiveness. Aging is the greatest risk factor for breast cancer. We have proposed that understanding the mechanisms by which age increases susceptibility to breast cancer is crucial for developing a prevention strategy. We showed that the loss of lineage fidelity in luminal epithelial cells is a striking hallmark of aging, and of overall increased susceptibility, in breast. This is significant because luminal cells are thought to be the cell-of-origin for most breast cancers. Among the most prominent molecular changes in the loss of lineage fidelity is the downregulation of ELF5, a transcription factor crucial for maintaining young and healthy luminal cell states. Based on age-associated expression of ELF5, we developed an “ELF5 clock” that measures biological age in breast tissue, identifying women who are at high risk regardless of the specific monogenic trait or aging risk factors. Furthermore, we showed that ELF5 expression once lost can be regained in conditions that simulate a younger microenvironment, suggesting that ELF5 may identify both accelerated and decelerated biological aging. The ELF5 clock may therefore assess changes in the biological aging rates of breast tissue following treatment with potential breast cancer risk reduction agents. Our goal is to evaluate the ELF5 clock as a novel breast-specific biomarker for identifying biological responses in intervention trials using clinically obtainable breast biopsy samples. To address this goal we will (1) vet the ELF5 clock as a breast- specific biomarker in breast cancer prevention clinical trials. By evaluating retrospectively obtained cDNAs prepared from de-identified RPFNA samples from breast cancer prevention clinical trials. (2) We will increase the accuracy of the ELF5 clock by incorporating genes affected by and orthogonal to ELF5 and testing a multiple correlation strategy. This approach will help in identifying the first breast-specific outcome-associated biomarkers for treatments with interventions and in developing a tool for evaluating intervention trials for breast cancer prevention.
