Roles of E2F3 and SGO1 in the Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer - SUMMARY/ ABSTRACT
Despite the great advancements in breast cancer research and treatment, approximately 42,000
US women are expected to die from breast cancer in 2019. Especially deadly are basal, triple-
negative (TN) breast cancers. Basal TNBC are more prevalent in African American and Hispanic
women and there are no biological therapies available to treat them. The E2 Promoter Binding
Factors (E2Fs) are a group of eight transcription factors under retinoblastoma (Rb) control that
regulate several cellular processes including DNA replication, genomic stability and apoptosis.
Broadly, E2Fs can be divided into transcriptional activators (those that promote gene
transcription) and repressors (those that halt gene transcription). Preliminary data I present here
shows 67% basal/TN breast cancers overexpress the E2F activators. It is known that the Rb
pathway is involved in the epithelial-to-mesenchymal transition (EMT), an early process that lead
to metastasis; yet the involvement of the E2F activators driving EMT in breast cancer is still under
investigation. Our published data demonstrated that overexpression of E2F activators (E2F1-3)
leads to increased expression of mitotic regulators (MPS1, NEK2, SGO1, among others).
Furthermore, we recently published that that MPS1 promotes EMT and invasion and NEK2 (an
E2F target) generates pre-invasive protrusions in 3D culture models. Hence, we question to what
extent deregulation of E2Fs activators promotes EMT, invasion, and metastasis through SGO1.
Specifically, we will focus our research in E2F3 because it is overexpressed in 42% basal breast
cancers and it we already showed that E2Fs regulate the stability of SGO1 protein levels. Our
central hypothesis is that the overexpression of E2F3 contributes to tumorigenesis by promoting
EMT through the induction of the transcription of SGO1, thus leading to increased invasion and
metastasis. To test our central hypothesis, we will develop the following two specific aims: (1)
Determine the effects of E2F3 and SGO1 in EMT, invasion, and migration in metastatic, triple-
negative breast cancer cells. (2) Determine the effects of E2F3 knockout in MDA-MB-231 cell
lines using CRISPR/Cas9 genome editing in NOD scid gamma mouse models. We expect to
identify a mechanism of how E2F3 overexpression promotes EMT through SGO1 in breast
cancer, thus contributing to migration, invasion, and metastasis. If the expected outcomes are
met, small molecules may be designed to improve current therapies to target downstream
effectors of E2F3, since E2Fs cannot be targeted.
