Breast cancer represents the second leading cause of cancer-related deaths in the world. There is increasing evidence that perturbation of cell cycle regulation is an important contributing factor to various cancer progression stages. There are key checkpoints in the cell cycle involving various regulatory proteins. The relationship between these cell cycle regulatory proteins and cell cycle arrest by cyclo-oxygenase (COX) inhibitors during neoplastic progression remains largely unknown. Preclinical studies and epidemiological investigations have consistently shown that non-steroidal anti-inflammatory drugs have some anti-proliferative and anti-oxidative stress response on various tumors. In this study, the effect of etodolac, a 1,8-diethyl-1,3,4,9-tetrahydro-pyrano (3,4-beta) indole-1-acetic acid on signaling pathways was investigated by examining the differential expression of various cell cycle regulatory protein genes. A human cell cycle gene array was used to profile the expression of 96 genes involved in the cell cycle regulation. Differentially expressed genes were highly altered by etodolac treatment. Twenty-six genes were up- and 20 down-regulated with 0.5 and 2 mM etodolac treatment, respectively. Seven genes (ATM, BAX, CCNA2, CDC27, RAD50 and p21) were prominently altered, and six (ATM, CCND2, CCNF, CDC20, CDK1A and RAD50) were commonly altered with both concentrations. This finding indicated that etodolac could play a critical role on cancer cells by inducing cell death.