Targeting the EphB4 Receptor to Inhibit Breast Tumor Growth
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: EphB4 is a protein that is highly produced in malignant human breast tumors. In mouse models of breast cancer, EphB4 is present at high levels in the more aggressive and metastasizing mammary tumors. This suggests that EphB4 is a novel breast cancer marker and plays a role in tumor progression. A portion of EphB4 is exposed on the cell surface and binds the exposed portion of a protein called ephrin-B2. When this contact occurs, the portion of EphB4 that resides inside the cell transmits signals. In addition, this contact also causes ephrin-B2 signaling. Interestingly, ephrin-B2 is present in tumor blood vessels and is required for the formation of functional blood vessels in the developing embryo. Therefore, EphB4 in conjunction with ephrin-B2 may contribute to breast cancer progression by affecting the properties of both tumor cells and tumor blood vessels. Our hypothesis is that the portion of EphB4 that is exposed on the outer surface of tumor cells binds ephrin-B2 in blood vessels, and this stimulates the formation of blood vessels that feed the tumor and promote its growth. Conversely, activation of EphB4 signaling within the tumor cells may inhibit tumor cell growth. Indeed, preliminary evidence from our laboratory shows that engineering high production of only the outer portion of EphB4 in a breast cancer cell line increases the growth rate of tumors in a mouse breast cancer model. We propose here to confirm these effects in different breast cancer cells to determine whether they have general relevance in different breast cancer models. The specific aims are:
 
 
 
 
 
 
 
 Aim 1. Screen human breast cancer cell lines for EphB4 expression and signaling. In the human breast cancer cell line that we used previously as a model to study the role of EphB4 in tumor growth, EphB4 is present at moderate levels and signals only weakly. In this aim we will screen a number of other breast cancer cell lines to determine their level of EphB4 expression and signaling. The goal is to identify a cell line with high EphB4 signaling activity to use for the experiments described in Aim 2.
 
 
 
 
 
 
 
 Aim 2. Determine whether high production on the tumor cell surface of an EphB4 protein that lacks signaling capability promotes tumor growth in different breast cancer models. The human breast cancer cell line identified in Aim 1 will be engineered to produce high levels of the outer portion of EphB4 on its surface. This should increase EphB4 interactions with ephrin-B2 and at the same time decrease overall EphB4 signaling. These cells will be injected in the mammary gland region of nude mice to generate tumors. We will then compare the rate of tumor growth and the formation of blood vessels in tumors derived from the engineered cells and from control cells. Nude mice are an established model system to study human cancers.
 
 
 
 
 
 
 
 These studies will determine the general role of EphB4 in breast cancer progression. They will also form the basis for designing anti-breast cancer treatments that target the EphB4 receptor in order to inhibit tumor growth.