Targeting the ubiquitin-proteasome pathway in breast cancer.
The 26S proteasome is an adenosine triphosphate-dependent multicatalytic protease that is responsible for most nonlysosomal intracellular protein degradation. To be selected for proteasomal degradation, proteins must be previously tagged with a polyubiquitin chain, which is then recognized by the proteasome; the ubiquitin chain is removed by isopeptidases and the protein is hydrolysed to small polypeptides. In addition to removing damaged/unnecessary proteins, the proteasome is also an important mechanism of regulation of some key regulatory proteins and their inhibitors. This regulation is crucial for the control of many cellular processes, including activation of transcription factors, cell cycle progression, and apoptosis. The critical role of the ubiquitin-proteasome pathway in tumor cells has led to the investigation of proteasome inhibition as a potential anticancer therapy. The dipeptide boronic acid analogue bortezomib, formerly known as PS-341, is a potent, highly selective, and reversible proteasome inhibitor. The first drug of this class to be used in the clinical setting, it has recently been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and is currently being tested in clinical trials for the treatment of a wide variety of malignancies. This article provides a summary of the biology of the ubiquitin-proteasome pathway, reviews the available preclinical and clinical data of proteasome inhibition as a therapeutic strategy in breast cancer, and discusses future combination regimens involving bortezomib.
Cardoso
Fatima
F
Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium. fatima.cardoso@bordet.be
Ross
Jeffrey S
JS
Picart
Martine J
MJ
Sotiriou
Christos
C
Durbecq
Virginie
V
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D008967:Molecular Biology; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015996:Survival Rate; D016896:Treatment Outcome; D025801:Ubiquitin / Q000494:pharmacology* / Q000627:therapeutic use
D001897:Boronic Acids; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex