Cancer often involves alterations in signaling pathways that result in a plethora of tyrosine phosphorylated substrates. However, most of the tyrosine kinases that are responsible for this signaling are unknown. The long-term goal of our research is to identify and establish the functional relevance of tyrosine kinases that are overexpressed in cancer cells. Specifically, we have sought to identify novel kinases responsible for the elevated tyrosine phosphorylation in breast cancer cells. We focused our attention upon one particular tyrosine kinase, EphA2, which is highly expressed in metastatic breast cancer cells. Further study documented that the expression of this molecule responded to the transformed state of the cells. In particular, EphA2 expression is regulated by estrogen, Myc and E-cadherin all of which have important roles in breast cancer progression. We have found that the tyrosine kinase activity of EphA2 localizes with E-cadherin to cell-cell junctions in normal epithelia. Upon transformation to metastasis, EphA2 redistributes throughout the membrane and is grossly overexpressed (>20x). Our preliminary studies also indicate that EphA2 and HER2 identify distinct populations of breast cancer cells. In this application, we wish to address questions that are logical extensions of our preliminary results: 1) does over-expression of EphA2 expression conveys diagnostic information? 2) How do EphA2 levels in pathology specimens relate to molecules that regulate its expression and function in cell culture models? To answer these questions, we will measure EphA2 overexpression as a function of tumor grade using immunohistochemistry. We will also perform co-variate analyses to relate EphA2 expression with molecules that regulate it in vitro: ER, Myc, and E-cadherin controls EphA2 subcellular localization. Finally, we will determine if EphA2 and HER2 are overexpressed in distinct populations of breast cancer cells.
| Walker-Daniels, Jennifer; Hess, Angela R; Hendrix, Mary J C et al. (2003) Differential regulation of EphA2 in normal and malignant cells. Am J Pathol 162:1037-42 |
| Zantek, N D; Walker-Daniels, J; Stewart, J et al. (2001) MCF-10A-NeoST: a new cell system for studying cell-ECM and cell-cell interactions in breast cancer. Clin Cancer Res 7:3640-8 |
