In situ to invasive carcinoma transition: escape or release

To identify molecular alterations involved in the initiation and progression of breast carcinomas in all cell types composing the breast, we generated Serial Analysis of Gene Expression (SAGE) libraries from purified epithelial, myoepithelial, endothelial cells, infiltrating leukocytes, and fibroblasts from normal breast tissue, and in situ and invasive breast carcinomas. Based on these SAGE data and follow-up studies using mRNA in situ hybridization and immunohistochemistry, we determined that dramatic gene expression changes occur not only in the epithelial (cancer) cells, but in various stromal cells as well. We found that the most consistent and dramatic gene expression changes during breast tumor progression occur in myoepithelial and myofibroblasts cells and the majority of aberrantly expressed genes encode secreted proteins or cell surface receptors. Interestingly the receptors for several chemokines upregulated in myoepithelial cells and/or myofibroblasts are expressed by epithelial cells. Moreover, we demonstrated that these stromal chemokines enhance the growth, migration, and invasion of breast cancer cells in vitro. Based on these data we propose that abnormal paracrine interactions between epithelial and myoepithelial/myofibroblasts cells, mediated in part by chemokines, may play a role in breast tumorigenesis and the progression of in situ carcinomas to invasive tumors.