The behaviour of breast cancer cells is strongly influenced by stromal and other neighbouring cells. However, the details of how different components of the surrounding tissue contribute to this are not well understood. A recent Cancer Cell paper provides evidence that all cell types in mammary tissue undergo changes in gene expression during cancer progression, indicating that each of these components contributes to the development of breast cancer.

Kornelia Polyak and colleagues studied gene expression in cells from normal breast tissue, ductal carcinoma in situ (DCIS; a pre-invasive tumour type) and invasive breast carcinomas. They first separated the various cellular components — including epithelial cells, myofibroblasts and myoepithelial cells, and stromal cells — using magnetic beads bound to antibodies against cell-type-specific markers.

The authors then used the serial analysis of gene expression (SAGE) method to obtain transcriptional profiles for the separated pools of cells. For each population, a set of genes was defined that was expressed at a higher level than in any of the other cell types. Based on this data, a clustering algorithm was then used to determine how related the transcription profiles were between cells of the same type from different stages in tumour progression. This showed that for each cell type there was a progressive change in gene expression from normal tissue, through DCIS and finally to invasive carcinoma. This provides strong evidence that all the cell types in breast tissue — not just the epithelial cancer cells themselves — undergo molecular changes during tumour progression.

Many of the genes upregulated in the stromal and other neighbouring cell types in DCIS and invasive carcinomas were found to encode secreted molecules and receptor proteins. These included several proteases and protease inhibitors, consistent with the generally accepted role of these cell types in contributing to tumour progression mainly through processes such as matrix remodelling that promote migration and invasiveness. However, in support of recent studies indicating that these cells are also involved in signalling to cancer cells, a significant proportion of the upregulated genes encoded proteins with signalling functions, such as chemokines, interleukins and growth-factor receptors.

In light of this, the authors looked in more detail at the role of two signalling molecules — the chemokines CXCL12 and CXCL14 — that were upregulated in cancer tissue in myofibroblasts and myoepithelial cells, respectively. Both of these chemokines stimulate the growth, migration and invasiveness of breast cancer cells in vitro. Polyak and colleagues found that the receptors for both chemokines were expressed in epithelial cells at higher levels in invasive tumours than in DCIS or normal tissue. In addition, they showed that epithelial cells adjacent to the myoepithelial layer show an increased rate of proliferation in vivo. So, myoepithelial cells and myofibroblasts provide paracrine signals that might be important for several stages of tumorigenesis.

Further investigation of the genes that are differentially expressed in cell types surrounding cancer cells should provide more clues to the molecular changes that drive breast cancer development. Identifying these changes might also provide opportunities to develop therapeutic strategies that target stromal and mesenchymal cells, as well as cancer cells themselves.