Keratinocyte induced chemotaxis in the pathogenesis of Paget's disease of the breast

In Paget's disease of the breast, the epidermis contains large clear neoplastic cells. To explain the pathogenesis of this disease, the immunohistochemical characteristics of these cells were investigated in 25 patients. The cytoplasmic presence of low molecular weight cytokeratin and the absence of high molecular weight cytokeratin in all cases confirmed the glandular origin of the Paget cells. Membrane over-expression of the neu-protein was established in 96% of cases. It was hypothesized that epidermal keratinocytes release a chemotactic factor which attracts neu-over-expressing breast carcinoma cells by chemotaxis into the epidermis. The biological assays showed that normal keratinocytes release one or more chemotactic factor(s) into their conditioned medium, which induced spreading and motility of neu-over-expressing SK-BR-3 human breast cancer cells. The conditioned medium of keratinocytes also attracted the SK-BR-3 cells by chemotaxis in a modified Boyden chamber. Furthermore, MCF-7 human breast cancer cells, which do not over-express the neu-protein, were not attracted by chemotaxis of conditioned medium of human keratinocytes. The involvement of the neu-protein in spreading, motility and chemotaxis is further indicated by the inhibition of these processes by monoclonal antibodies against the extracellular domain of the neu-protein. We conclude, therefore, that the Paget cells spread through the epidermis due to the motility induced by a chemotactic factor, which is released by epidermal keratinocytes and whose influence is mediated by the neu-protein.