Targeting the ubiquitin-proteasome pathway in breast cancer therapy.

The ubiquitin-proteasome pathway (UPP) is the major eukaryotic mechanism for regulated intracellular proteolysis. Targeting this pathway with proteasome inhibitors has been validated as a rational strategy against hematologic malignancies, but for most solid tumor populations, including breast cancer, such agents have not shown encouraging activity. However, there is an increasing body of evidence showing that UPP dysregulation plays an important role in mammary tumorigenesis. Moreover, modulation of ubiquitin-proteasome function is emerging as a rational strategy to enhance chemosensitivity and overcome chemoresistance. Taken together, these facts suggest that we are only beginning to appreciate the relevance of this pathway for the current and future therapy of patients with breast cancer. This review provides an overview of the biology of the UPP, its role in the malignant process, the current state of knowledge regarding clinical heat shock protein and proteasome inhibition, and some likely future directions that may enhance our ability to exploit this pathway therapeutically.