Identification of gene-expression signatures associated with organ site-specific metastasis. The procedure followed by Massagué and colleagues [3,4] was as follows. (a) Selection of stable lung- and bone-metastatic sublines of MDA-MB-231 cells in vivo. (b) Comparison of their gene-expression patterns with parental cell lines. (c) Validation of the role of signature genes in metastatic activity by confirming that selected genes when overexpressed or underexpressed alone or in combination altered the site-specific metastatic activity of the parental line. (d) The lung signature defined from the above study was predictive of metastatic activity in an independent clinical cohort of breast cancer patients.