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PKCaand Ets1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCaexpression (siPa) by RNA interference leads to reduced Ets1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPainterferes with both Ets1 protein synthesis and stability. The effect of siPaon Ets1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of Ets1 activity, may play a role in PKCa-dependent Ets1 regulation. In contrast, Ets1-regulating kinases ERK1/2 were not found to be involved in this process. To assess the importance of the PKCa/Ets1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCa- and Ets1-specific siRNAs (siE1). While only siPainduced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPaand siE1. The data suggest that Ets1 serves as an effector for PKCato fulfil certain functions in cancer cells.Oncogene (2005) 24, 650-661. doi:10.1038/sj.onc.1208234 Published online 8 November 2004 [ABSTRACT FROM AUTHOR]