Graduate Student Sanford Burnham Prebys La Jolla, California, United States
Abstract: Aging is the primary risk factor for adult cancers, including breast cancer, yet mechanisms for this relationship are not entirely understood. Recent studies highlight how disruptions in cellular homeostasis, driven by age-associated epigenetic alterations, contribute to cancer progression. Using a mouse model of breast cancer induced by intraductal injection of the Erbb2 oncogene, we observed increased tumorigenesis in older mice compared to younger ones. In aged mice, Erbb2 positive cells upregulated epithelial-to-mesenchymal transition marker genes, while downregulating chemokines, thereby increasing recruitment of anti-tumor immune cells and altering cell identity. Given that aging drives tumor-promoting changes at the molecular level, an emerging question is whether reversing age-related alterations can mitigate cancer risk. Multiple groups have demonstrated that tissues can be rejuvenated via transient induction of Yamanaka factors. This process reverses age-related molecular changes, restoring a youthful state without dedifferentiating cells or promoting tumorigenesis. Building on these findings, our project investigates whether epigenetic rejuvenation can restore homeostasis and suppress cancer development in aged tissues. To achieve this, we are developing a partial reprogramming strategy to correct age-associated changes in the mammary epithelia. This approach aims to reverse transcriptomic alterations and cell identity drifts, with the goal of enhancing tissue homeostasis prior to oncogenic challenge. By applying this strategy in-vivo, we aim to assess its effects on tumor initiation, progression, and immune infiltration in young and old mice. Advanced techniques, such as GeoMX and single-nuclei RNA sequencing, will be used to uncover the molecular drivers underlying these effects. This research bridges the fields of stem cell biology, cancer and aging, and has the potential to revolutionize cancer prevention in high-risk individuals by targeting the cellular dysfunctions that arise with age.
Funding Source: Sanford Burnham Prebys Cancer Center
