2006 Ohio Student Research Forum

Abstract

The Role of E2F Transcriptional Activators in Oncogene Mediated Mammary Tumorigenesis
Jackie Johnson
Ohio State University
Department of Molecular Genetics
Mentor: Dr. Gustavo Leone and Dr. Lizhao Wu

In the past two decades, various studies, including those using animal models, have significantly enhanced our understanding about the molecular basis of breast cancers. One major finding is that over-expression of various oncogenes is a driving force for many breast cancers. For example, over-expression of the ErbB2 (Neu) oncogene or Myc oncogene has been found in up to 30% of breast cancer patients. These oncogenes are believed to function as growth stimulators upstream of the retinoblastoma tumor suppressor (Rb), which plays a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2 and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition of the cell cycle. Because of the link between the Rb/E2F pathway and oncogene-mediated signaling, it is likely that E2F activators play an essential role in oncogene-mediated mammary tumorigenesis. To test this hypothesis in vivo conditional and conventional knockout mouse models were used to determine the effect of deletion of E2F1, E2F2, and E2F3 on normal mammary gland development and on oncogene-induced mammary carcinomas by examining mammary glands at various stages of the development and final tumors induced by the activation of Myc or Neu oncogenes. Here we show that deletion of E2F1 delays mammary tumorigenesis in the Neu model but not in the Myc model, suggesting oncogene specificity on E2F1. Although deletion of E2F3 has no significant impact on mammary gland development, under oncogenic influence it leads to a significant delay of mammary tumor onset and a slight reduction of proliferation in pre-tumor state but not in the final tumors, suggesting that E2F3 is important for Myc- and Neu-induced mammary tumorigenesis. Consistent with a critical role of E2F3 in oncogene-mediated signaling in the mammary glands, in final tumors the E2F3 deletion efficiencies are reduced from ~33% in Neu;E2F3^+/f mice or Myc;E2F3^+/f mice to 22.5% in Myc;E2F3^-/f mice and 12.1% in Neu;E2F3-/f mice, indicating a strong selection against E2F3 mutant cells to form tumors in both models, with a stronger selection pressure in the Neu model. In further supporting the important role of E2F3 in oncogene-induced mammary tumorigenesis, E2F3a is up-regulated in a majority of mouse mammary tumors with Myc- or Neu- over-expression, and up-regulated in a subset of human breast cancer patients with Neu (Her2) over-expression. Taken together, our data suggests that E2F3 is a critical downstream effector of Myc- and ErbB2-mediated signaling in the mammary glands and may provide insights on E2F3-based targeted therapy of human breast cancers.