Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) protects epit helial and cancer cells against DNA-damaging agents via a pathway involving signaling from c-Met --> phosphatidylinositol-3-kinase --> c-Akt. However, the downstream alterations in gene expression resulting from this pathway have not been established. On the basis of cDNA microarray and semiquantita tive RT-PCR assays, we found that MDA-MB-453 human breast cancer cells prei ncubated with HGF/SF and then exposed to Adriamycin (ADR), a DNA topoisomer ase II inhibitor, exhibit an altered pattern of gene expression, as compare d with cells treated with ADR only. [HGF/SF+ADR]-treated cells showed alter ed expression of genes involved in the DNA damage response, cell cycle regu lation, signal transduction, metabolism, and development. Some of these alt erations suggest mechanisms by which HGF/SF may exert its protective activi ty, e.g., up-regulation of polycystic kidney disease-1 (a survival-promotin g component of cadherin-catenin complexes), downregulation of 51C (an inosi tol polyphosphate-5-phosphatase), and downregulation of TOPBP1 (a topoisome rase IIB binding protein). We showed that enforced expression of the cdc42- interacting protein CIP4, a cytoskeleton-associated protein for which expre ssion was decreased in [HGF/SF+ADR]-treated cells, inhibited HGF/SF-mediate d protection against ADR. The cDNA microarray approach may open up new aven ues for investigation of the DNA damage response and its regulation by HGF/ SF.