Abstract P1-03-09: The role of E2F5 in breast cancer progression and metastasis

Abstract

Abstract Advances in cancer genomics and transcriptomics have provided a better understanding of the diverse genetic landscape driving breast cancer pathogenesis. Despite these advances, the molecular drivers of triple negative breast cancer, an aggressive and heterogenous disease, remains highly elusive. Utilizing a genomic approach, we examined genetic differences across mouse models of breast cancer and identified a gene that was consistently deleted in basal-like mouse models, the predominant intrinsic subtype of triple negative breast cancer. Specifically, we identified a consistent deletion in the transcription factor E2F5. In human breast cancer, E2F5 activity and expression is associated with better overall survival and relapse free survival. To further study the role of E2F5 in breast cancer, E2F5 was deleted in the mammary gland of FVB mice (E2F5cKO) through the use of a cre-lox system driven by the MMTV promoter. E2F5cKO mouse demonstrated a delay a mammary outgrowth, suggesting a potential role in mammary gland development. E2F5cKO mice were aged and observed for tumor development. This revealed mammary tumor formation after an extended latency of 19 months. The resulting mammary tumors demonstrated diverse histological patterns. E2F5cKO tumors also demonstrate high metastatic potential with 70% of tumor bearing mice developing metastasis to the lung. In addition, E2F5cKO tumors have a propensity to metastasize to axillary lymph nodes when transplanted into MMTV-Cre mice, a unique feature that is not commonly observed in other mouse models of breast cancer. To begin to understand the mechanism of tumor progression in E2F5cKO mice, differential gene expression was performed on gene expression data derived from E2F5 or GFP overexpression Human Mammary Epithelial Cells. The resulting differentially expressed genes were further filtered based on fold change, established role in cancer, potential E2F binding site and gene ontology. One of the leading candidates that arose from this analysis was KRas, an oncogene that is highly implicated in tumorigenesis. KRas expression negatively correlated with E2F5 expression. Using a bioinformatic approach, we demonstrated that this inverse relationship between KRas and E2F5 appears to be conserved in human breast cancer. Given this inverse relationship between E2F5 and KRas, we postulate that E2F5 deletion in the mammary gland of mice leads to increased KRas activity. Consistent with our hypothesis, western blot analysis revealed high activity in two major KRas signaling pathways, Akt and Erk, in the majority of E2F5cKO tumors. Together, this preliminary data suggest that E2F5 may behave as a tumor suppressor by negatively regulating the oncogene KRas. Citation Format: Briana To, Eran Robert Andrechek. The role of E2F5 in breast cancer progression and metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-09.