Reversion toward an earlier stage of differentiation and loss of polarity during progression of N-methyl-N-nitrosourea-induced rat mammary tumours.

To work toward an understanding of the mechanisms of cancer progression, we have followed the changes in expression of several genes in rat mammary carcinomas during the development of invasion. Tumors were induced by N-methyl-N-nitrosourea and serially transplanted to isogeneic rats. Gene expression in individual cells was followed by immunofluorescence microscopy. We show that invading cells do not express the same genes as the primary tumor or normal adult mammary gland but are similar to the primitive mammary duct cells present in late embryos. In the most advanced tumors, the most fundamental epithelial characteristic, polarity, is lost. Relative to the mechanism of invasion, we observe that the basal lamina, often thinner than normal, always coats the strands of invading cells and may be entirely absent from single invasive cells only. These observations suggest that the basal lamina ultimately disappears because of reduced expression of the genes or the failure to assemble the components. In these tumors it is the progressive alteration in gene expression rather than the enzymatic breakdown of the basal lamina that leads to invasion. These results show that the most important aspect of cancer progression is the progressive alteration of gene expression. They also raise questions about the mechanism that causes tumor cells to retrace the steps in their differentiation.