The role of the tumor microenvironment in breast cancer progression

Excerpt

We performed comprehensive molecular analysis of each cell type composing normal breast tissue and in situ and invasive breast carcinomas. Gene expression profiles were analyzed using serial analysis of gene expression, genetic changes were analyzed by single nucleotide polymorphism arrays, while epigenetic changes were analyzed using methylation-specific digital karyotyping. Based on these data we determined that gene expression and epigenetic changes occur in all cell types during breast cancer progression, while genetic alterations were only detected in tumor epithelial cells. Many of the differentially expressed genes encode for secreted proteins and receptors suggesting alterations in autocrine and paracrine interactions in breast tumorigenesis. Two of these genes, the CXCL14 and CXCL12 chemokines, overexpressed in tumor myoepithelial cells and in myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. Chemokines may thus play a role in breast tumorigenesis by acting as paracrine factors. The role of these chemokines, and myoepithelial and stromal cells in the progression of in situ carcinomas to invasive carcinomas was investigated using a xenograft model of human ductal carcinoma in situ. Based on our studies we determined that changes in the tumor microenvironment and epithelial–myoepithelial and epithelial–stromal cell interactions play an important role in breast tumor progression. …