Diminished feedback regulation of proteasome expression and resistance to proteasome inhibitors in breast cancer cells.
Clinical trials with proteasome inhibitor Bortezomib (also named Velcade or PS-341) has shown promising results for some cancers. However, other types of cancers including breast cancer do not respond well to Bortezomib. To understand the cause of the drug resistance, we compared the regulation of proteasome expression and the sensitivity to proteasome inhibitors between human breast cancer cells and nontumorigenic mammary epithelial cells. We found that, while the endogenous expression level is much higher, the potential of feedback expression in response to proteasome inhibitors is much lower in the breast cancer cells. Furthermore, the breast cancer cells are much more resistant to proteasome inhibitors compared to the nontumorigenic mammary epithelial cells. Biochemical analysis showed that the pathway of Bortezomib-induced apoptosis is apparently defective in the breast cancer cells. Together, these results provide an explanation for the inefficacy of Bortezomib in the clinical trials for breast cancer patients. The likelihood of combination therapy with Bortezomib and other anti-cancer agents for breast cancer is also discussed.
Xu
Haiming
H
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Ju
Donghong
D
Jarois
Tiffany
T
Xie
Youming
Y
D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D001897:Boronic Acids; D007976:Leupeptins; D011480:Protease Inhibitors; D011719:Pyrazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C022616:thiazolyl blue; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde