The EGF system, perhaps in concert with other growth factor systems, plays a central role in human breast cancer. Levels of expression of the EGF receptor have been inversely correlated with the prognosis of the disease in humans and transgenic animals that overexpress one of the ligands for this receptor, TGFalpha, develop epithelial hyperplasia and carcinoma in the mammary gland. Estrogen regulation of breast cancer cell growth has also been partially attributed to the ability of this hormone to upregulate TGRalpha gene expression. Signaling through the EGF system may be under other complex controls. One such control could derive from regulation of the ability of the EGF receptor to signal in response to ligands. For some years, it has been appreciated that an alternate form of EGF receptor consisting of a soluble extracellular domain (ectodomain) is expressed by cancer cells and normal tissues. This segment of the receptor can bind ligand and may even be able to interact with the classical transmembrane receptor-tyrosine kinase to modulate ligand induced signal transduction. The ectodomain is produced as a result of alternate splicing of the EGF receptor transcript. We propose to study the EGF receptor ectodomain as a potential modulator of breast cancer growth and mammary gland development. We have produced milligram quantities of this molecule in a vaccinia virus system and have purified it to near homogeneity on a monoclonal antibody column. We will study the effect of this reagent on breast cancer cell growth in culture and correlate these effects with those on EGF receptor signal transduction. We will also study the effect of the ectodomain on the progression of human breast cancer in nude mice. Finally, we propose to create a transgenic mouse model in which overexpression of the ectodomain is targeted to the mammary gland using the MMTV-LTR as a promoter. These studies will form the basis for understanding the role of the EGF receptor signalling system in mammary gland development and breast cancer progression. This basic knowledge has the potential of developing into clinical applications for breast cancer and should be superior to the current protocols of using mouse derived monoclonal antibodies to the EGF receptor. This advantage relates to the observation that the EGF receptor ectodomain is a normal product of the EGF receptor gene.
