The Proteasome as a Novel Target for the Treatment of Breast Cancer1

Abstract

The 26S proteasome is a promising new target for breast cancer therapy. The degradation of proteins by the proteasome is an essential metabolic process, and inhibition of the proteasome results in cell-cycle arrest and apoptosis. However, cancer cells and proliferating blood vessels appear to be particularly sensitive to the effects of proteasome inhibition. Studies carried out in breast cancer cells and murine xenograft models of breast cancer have demonstrated the potent antitumor effects of proteasome inhibition in this disease. Proteasome inhibition interferes with many cell signaling pathways, including those involved in the development and progression of breast cancer. The potent and selective proteasome inhibitor bortezomib (VELCADE; formerly known as PS-341) is particularly promising as a potential anticancer agent. PS-341 is the first proteasome inhibitor to be extensively studied in murine models of cancer and to progress to clinical trials in cancer patients. Preliminary clinical data from patients with a range of malignancies indicate that the drug effectively inhibits proteasome activity at doses associated with manageable toxicity. Early clinical trials are currently recruiting participants for the analysis of PS-341 activity in breast cancer.