A Novel Epithelial-Stromal Model of Metastatic Breast Cancer
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: Metastases, rather than primary tumors, are responsible for most breast cancer related deaths. Yet, we know little about this disease and lack effective animal model systems with which to test effective therapeutics that prevent or treat metastasis. We have identified the receptor tyrosine kinase, EPHA2, as a potential critical regulator of metastasis. In this proposal we will utilize an animal model of the human breast to study how EPHA2 and its ligand, EFNA1, control normal and malignant biology of the breast. 
 
 
 
 
 
 
 
 EPHA2 is strongly and specifically expressed in the subset of breast cancers that are predisposed to metastasis. We found EPHA2 and EFNA1 expression is highly compartmentalized in normal breast tissue and EFNA1 expression is lost in invasive cancers. Therefore we will test the hypothesis that EPHA2-EFNA1 interactions in the human breast maintain normal tissue integrity and that loss of EFNA1 is an initiating event in the pathogenesis of metastasis in a subset of breast cancers. Thus, our aims are to provide evidence for a causal role of EPHA2 in breast cancer metastasis. As part of this we aim to use a model that closely reflects the human breast microenvironment. This type of model will provide a more accurate interpretation of gene function in human cancer than existing model systems. We will manipulate gene expression of EPHA2 and EFNA1 in the epithelial and stromal compartments of the breast to identify their impact on morphology and histopathology of the normal breast and metastatic cancer. For these studies, we will use a technique that recapitulates a human mammary gland in the mouse. Combinations of human epithelial and stromal cells from normal or cancerous tissue will be mixed together and implanted under the renal capsule of the mouse. The cells can be manipulated to express specific genes of interest prior to implantation in mice. In this way we can create tissue that can reflects either the normal or the diseased state of a human breast. By studying the morphology, histopathology and metastatic potential of these recombinants we will establish how EPHA2 regulates epithelial morphogenesis and identify whether it plays a causal role in metastasis.
 
 
 
 
 
 
 
 This research has two potential area of impact. First, it will provide a powerful model to identify how epithelial-stromal interactions affect the mechanisms of breast cancer progression, a process still poorly understood for the human disease. Understanding these mechanisms has significant translational potential for therapeutic development. Secondly, it will serve as a “second generation” pre-clinical screen for therapeutic agents. Currently there is a high rate of failure in early phase clinical trials of drugs which showed robust response in mouse xenograft models. A model such as this that more closely resembles the human disease may yield more accurate therapeutic responses.