Overexpression of the receptor tyrosine kinase EphA2 induces malignant transformation of benign mammary epithelia: Implication for increased cell survival and altered cellular adhesions in breast cancer

Tissue function is supported through dynamic and reciprocal communication between cells and the tissue environment. Tyrosine phosphorylation is an important example of a mediator of this communication. Elevated levels of protein tyrosine phosphorylation promote malignant growth and behavior, although the tyrosine kinases that are responsible for this signaling remain largely unknown. Antibodies were generated against tyrosine phosphorylated proteins in malignant tissue in an attempt to identify tyrosine kinases responsible for the malignant phenotype. Here we report increased levels of the EphA2 (ECK) receptor protein tyrosine kinase in clinical specimens and cell models of breast cancer. Overexpression of EphA2 is sufficient to induce malignant transformation and tumorigenesis in non-transformed mammary epithelial cells. Specifically, common in vitro and in vivo assays identified increased survival in a foreign environment and alterations in cell adhesions as phenotypes of the EphA2 transformed cell, MCFEphA2. A major contributor to at least the alteration in cell adhesions provoked by EphA2 overexpression is increased production of the ECM component fibronectin. Further analysis of the balance of cell adhesions in nontransformed tissue reveals that the strength of ECM attachments adversely affects the strength of cell-cell adhesions. Additional studies revealed that the steroid sex hormone estrogen and the transcription factor Myc suppress EphA2 expression. This study depicts EphA2 as a regulator of malignant transformation, which may provide a novel target cancer therapeutics and diagnostics.