The heterogeneous nature of breast tumours results in widely divergent metastatic behaviour. Recently, it has been possible to correlate certain tumour-gene-expression signatures with either good or poor patient prognosis. Massagué and colleagues have taken this classification one step further, using microarray analysis to identify genes that selectively mediate the metastasis of breast cancer cells to the lung.

When breast cancers metastasize, they frequently spread to either bone or the lungs, through unknown mechanisms of tropism. Massagué's group investigated this tropism by carrying out gene-expression analysis on breast cancer cells that had been selected for their ability to metastasize to the lung in mice. When the authors compared the transcriptomes of breast cancer cell lines with varying metastatic properties, they identified 54 candidate genes that the authors proposed were involved in either baseline lung-metastatic functions or lung-restricted, specialized functions that conferred lung-metastatic virulence.

In particular, high expression levels of genes encoding the cell-adhesion molecule SPARC, the cell-adhesion receptor VCAM1 and matrix metalloproteinase 2 (MMP2) were detected in highly metastatic cells. Other genes — including ID1 , which encodes a transcriptional inhibitor of cell differentiation and senescence, and MMP1 — increased in relation to the lung-metastatic ability of the cell line.

When the authors overexpressed combinations of these genes in the parental cell line, they found that certain combinations conferred high levels of lung-selective metastatic activity. Furthermore, reducing the expression of some of these genes using RNA interference could decrease the lung-metastatic activity of the selected cells. Therefore, these genes are both markers and functional mediators of lung-selective metastasis.

To obtain clinical validation of their experimental findings, the authors analyzed expression levels of these genes in a cohort of human primary breast cancers. Patients with tumours expressing these genes had a poor lung-metastasis-free survival time, but expression of these genes did not correlate with bone-metastasis-free survival. Further analysis revealed that several of these lung-metastasis genes also facilitated breast tumorigenicity, which would explain how cells expressing these genes can be selected for in the primary tumour. Expression of other genes that are found in highly metastatic cells, however, is rare in primary tumours and does not significantly promote their growth, but once these rare cells reach the lung these genes are strongly selected for.