Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype.
Overexpression of cyclin E in breast tumors is associated with a poor response to tamoxifen therapy, greater genomic instability, more aggressive behavior, and a poor clinical prognosis. These tumors also express low molecular weight isoforms of cyclin E that are associated with higher kinase activity and increased metastatic potential. In the current study, we show that cyclin E overexpression in MCF7 cells transactivates the expression of calpain 2, leading to proteolysis of cyclin E as well as several known calpain substrates including focal adhesion kinase (FAK), calpastatin, pp60src, and p53. In vivo inhibition of calpain activity in MCF7-cyclin E cells impedes cyclin E proteolysis, whereas in vivo induction of calpain activity promotes cyclin E proteolysis. An analysis of human breast tumors shows that high levels of cyclin E are coincident with the expression of the low molecular weight isoforms, high levels of calpain 2 protein, and proteolysis of FAK. Lastly, studies using a mouse model of metastasis reveal that highly metastatic tumors express proteolyzed cyclin E and FAK when compared to tumors with a low metastatic potential. Our results suggest that cyclin E-dependent deregulation of calpain may be pivotal in modifying multiple cellular processes that are instrumental in the etiology and progression of breast cancer.
Libertini
Stephen J
SJ
Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California 95616, USA.
Robinson
Brian S
BS
Dhillon
Navdeep K
NK
Glick
Danielle
D
George
Michael
M
Dandekar
Satya
S
Gregg
Jeffrey P
JP
Sawai
Earl
E
Mudryj
Maria
M
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis; D015533:Transcriptional Activation; D014162:Transfection
D019927:Cyclin E; D007527:Isoenzymes; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002154:Calpain