Research article

The expression of the ubiquitin ligase subunit Cks1 in human breast cancer

Merav Slotky¹ , Ma'anit Shapira¹ , Ofer Ben-Izhak² , Shai Linn⁴ , Boris Futerman⁴ , Medy Tsalic³ and Dan D Hershko^1,5

¹  Department of Surgery A, Rambam Medical Center and the Technion–Israel Institute of Technology, Haifa, Israel

²  Department of Pathology, Rambam Medical Center and the Technion–Israel Institute of Technology, Haifa, Israel

³  Department of Medical Oncology, Rambam Medical Center and the Technion–Israel Institute of Technology, Haifa, Israel

⁴  Unit of Clinical Epidemiology, Rambam Medical Center and the Technion–Israel Institute of Technology, Haifa, Israel

⁵  Breast Health Institute, Rambam Medical Center and the Technion–Israel Institute of Technology, Haifa, Israel

author email corresponding author email

Breast Cancer Research 2005, 7:R737-R744doi:10.1186/bcr1278

Published:	19 July 2005

Abstract

Introduction

Loss of the cell-cycle inhibitory protein p27^Kip1 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 p27^Kip1 and Skp2 expression and to tumor aggressiveness.

Methods

The expressions of Cks1, Skp2, and p27^Kip1 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 p27^Kip1 (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.

Conclusion

These results suggest that Cks1 is involved in p27^Kip1 down-regulation and may have an important role in the development of aggressive tumor behavior in breast cancer.