Integrated transcriptome analysis of the cellular mechanisms associated with Ha-ras-dependent malignant transformation of the human breast epithelial MCF7 cell line

To understand the cellular mechanisms of malignant transformation induced by constitutive activation of the ras oncogene (Ha-ras), we used asubtractive hybridization method (VGIDTM) togetherwith an integrative analytical procedure based uponliterature databases in the form of extensive interaction graphs. We found 166 over- and underexpressed genes which, in the human MCF7-rasbreast epithelial cell line, are involved in the different aspects of tumoral transformation such asde®ned signaling pathways, cellular growth, protection against apoptosis, extracellular matrixand cytoskeleton remodeling. Integrative analysisled to the construction of a physiological modelde®ning cross-talk and signaling pathway alterations which explicitly suggested mechanismsdirectly involved in tumor progression. The modelfurther suggested points and means of interventionwhich could induce cell death in Ha-ras-transformedcells speci®cally. These hypotheses were directlytested in vitro and found to be largely correct,hence indicating that these new analytical andtechnological approaches allow the discovery ofpathology-associated cellular mechanisms andphysiologically de®ned targets leading to phenotype-speci®c pharmacological interventions