Rhoc GTPase is a multifunctional member of the family of ras homology proteins, which are involved in cytoskeletal organization and function. Previous studies of the genetic determinants of inflammatory breast cancer (IBC) revealed that Rhoc is overexpressed in 91% of IBC tumors but not in non-IBC tissue. We subsequently showed that RhoC is a transforming oncogene for immortalized mammary epithelial cells (HME), generating a highly invasive and angiogenic phenotype akin to IBC. We proposed that RhoC overexpression induces expression of genes for cytoskeletal activity, motility and angiogenic mediators. In order to analyze the pattern of gene expression stimulated by RhoC overexpression, we compared Rhoc-transfected mammary epithelial cells with cells that had not been transfected, using a microarray of 5,000 complementary DNAs. Rhoc induces the overexpression (7.88- to 1.45-fold) of 29 genes and decreases (0.8- to 0.3-fold) the expression of 8 genes. RhoC induces expression of key cytoskeletal structural genes, cell adhesion genes, membrane-associated genes, genes that control intracellular metabolism and genes involved in mediating angiogenesis. The pattern of gene expression suggests a model for signaling mechanisms activated by this important oncogene through activation of the cytoskeleton and motility. Tests of biological activity of several of these key genes reveal specific roles in the malignant phenotype induced by RhoC, further supporting the hypothesis that their expression contributes to invasion and angiogenesis. This work suggests specific therapeutic interventions for IBC.