The expression of the ubiquitin ligase subunit Cks1 in human breast cancer.
BACKGROUND
Loss of the cell-cycle inhibitory protein p27Kip1 is associated with a poor prognosis in breast cancer. The decrease in the levels of this protein is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1). Skp2 was recently found to be overexpressed in breast cancers, but the role of Cks1 in these cancers is unknown. The present study was undertaken to examine the role of Cks1 expression in breast cancer and its relation to p27Kip1 and Skp2 expression and to tumor aggressiveness.


METHODS
The expressions of Cks1, Skp2, and p27Kip1 were examined immunohistochemically on formalin-fixed, paraffin-wax-embedded tissue sections from 50 patients with breast cancer and by immunoblot analysis on breast cancer cell lines. The relation between Cks1 levels and patients' clinical and histological parameters were examined by Cox regression and the Kaplan-Meier method.


RESULTS
The expression of Cks1 was strongly associated with Skp2 expression (r = 0.477; P = 0.001) and inversely with p27Kip1 (r = -0.726; P < 0.0001). Overexpression of Cks1 was associated with loss of tumor differentiation, young age, lack of expression of estrogen receptors and of progesterone receptors, and decreased disease-free (P = 0.0007) and overall (P = 0.041) survival. In addition, Cks1 and Skp2 expression were increased by estradiol in estrogen-dependent cell lines but were down-regulated by tamoxifen.


CONCLUSIONS
These results suggest that Cks1 is involved in p27Kip1 down-regulation and may have an important role in the development of aggressive tumor behavior in breast cancer.
Slotky
Merav
M
Department of Surgery A, Rambam Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel. m_slotky@rambam.health.gov.il
Shapira
Ma'anit
M
Ben-Izhak
Ofer
O
Linn
Shai
S
Futerman
Boris
B
Tsalic
Medy
M
Hershko
Dan D
DD
D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D011494:Protein Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D021122:Protein Subunits; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases