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 a subtractive hybridization method (VGID) together with an integrative analytical procedure based upon literature databases in the form of extensive interaction graphs. We found 166 over- and under-expressed genes which, in the human MCF7-ras breast epithelial cell line, are involved in the different aspects of tumoral transformation such as defined signaling pathways, cellular growth, protection against apoptosis, extracellular matrix and cytoskeleton remodeling. Integrative analysis led to the construction of a physiological model defining cross-talk and signaling pathway alterations which explicitly suggested mechanisms directly involved in tumor progression. The model further suggested points and means of intervention which could induce cell death in Ha-ras-transformed cells specifically. These hypotheses were directly tested in vitro and found to be largely correct, hence indicating that these new analytical and technological approaches allow the discovery of pathology-associated cellular mechanisms and physiologically defined targets leading to phenotype-specific pharmacological interventions.
D000465:Algorithms; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D019295:Computational Biology / Q000379:methods*; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008962:Models, Theoretical; D009693:Nucleic Acid Hybridization / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015689:Oncogene Protein p21(ras)