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Breast Cancer Research

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Open Access 01-10-2005 | Research article

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

Authors: Merav Slotky, Ma'anit Shapira, Ofer Ben-Izhak, Shai Linn, Boris Futerman, Medy Tsalic, Dan D Hershko

Published in: Breast Cancer Research | Issue 5/2005

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.

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Morabito A, Magnani E, Gion M, Sarmiento R, Capaccetti B, Longo R, Gattuso D, Gasparini G: Prognostic and predictive indicators in operable breast cancer. Clin Breast Cancer. 2003, 3: 381-390.CrossRefPubMed

Tsihlias J, Kapusta L, Slingerland J: The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999, 50: 401-423. 10.1146/annurev.med.50.1.401.CrossRefPubMed

Alkarain A, Jordan R, Slingerland J: p27 deregulation in breast cancer: prognostic significance and implications for therapy. J Mammary Gland Biol Neoplasia. 2004, 9: 67-80. 10.1023/B:JOMG.0000023589.00994.5e.CrossRefPubMed

Chiarle R, Pagano M, Inghirami G: The cyclin dependent kinase inhibitor p27 and its prognostic role in breast cancer. Breast Cancer Res. 2001, 3: 91-94. 10.1186/bcr277.CrossRefPubMed

Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, et al: Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997, 3: 227-230. 10.1038/nm0297-227.CrossRefPubMed

Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M: Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997, 3: 231-234. 10.1038/nm0297-231.CrossRefPubMed

Tsihlias J, Kapusta LR, DeBoer G, Morava-Protzner I, Zbieranowski I, Bhattacharya N, Catzavelos GC, Klotz LH, Slingerland JM: Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 1998, 58: 542-548.PubMed

Hommura F, Dosaka-Akita H, Mishina T, Nishi M, Kojima T, Hiroumi H, Ogura S, Shimizu M, Katoh H, Kawakami Y: Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers. Clin Cancer Res. 2000, 6: 4073-4081.PubMed

Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995, 269: 682-685.CrossRefPubMed

10.

Hershko A, Ciechanover A: The ubiquitin system. Annu Rev Biochem. 1998, 67: 425-479. 10.1146/annurev.biochem.67.1.425.CrossRefPubMed

11.

Carrano AC, Eytan E, Hershko A, Pagano M: SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999, 1: 193-199. 10.1038/12013.CrossRefPubMed

12.

Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U, Krek W: p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999, 1: 207-214. 10.1038/12027.CrossRefPubMed

13.

Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H: p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol. 1999, 9: 661-664. 10.1016/S0960-9822(99)80290-5.CrossRefPubMed

14.

Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M: Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J Clin Invest. 2002, 110: 633-641. 10.1172/JCI200215795.CrossRefPubMedPubMedCentral

15.

Hershko D, Bornstein G, Ben-Izhak O, Carrano A, Pagano M, Krausz MM, Hershko A: Inverse relation between levels of p27(Kip1) and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer. 2001, 91: 1745-1751. 10.1002/1097-0142(20010501)91:9<1745::AID-CNCR1193>3.0.CO;2-H.CrossRefPubMed

16.

Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J, Krek W: Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci USA. 2001, 98: 5043-5048. 10.1073/pnas.081474898.CrossRefPubMedPubMedCentral

17.

Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC, Harper JW: Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res. 2002, 8: 3419-3426.PubMed

18.

Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A: The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Nat Cell Biol. 2001, 3: 321-324. 10.1038/35060126.CrossRefPubMed

19.

Spruck C, Strohmaier H, Watson M, Smith AP, Ryan A, Krek TW, Reed SI: A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Mol Cell. 2001, 7: 639-650. 10.1016/S1097-2765(01)00210-6.CrossRefPubMed

20.

Masuda TA, Inoue H, Nishida K, Sonoda H, Yoshikawa Y, Kakeji Y, Utsunomiya T, Mori M: Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma. Clin Cancer Res. 2003, 9: 5693-5698.PubMed

21.

Inui N, Kitagawa K, Miwa S, Hattori T, Chida K, Nakamura H, Kitagawa M: High expression of Cks1 in human non-small cell lung carcinomas. Biochem Biophys Res Commun. 2003, 303: 978-984. 10.1016/S0006-291X(03)00469-8.CrossRefPubMed

22.

Kitajima S, Kudo Y, Ogawa I, Bashir T, Kitagawa M, Miyauchi M, Pagano M, Takata T: Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. Am J Pathol. 2004, 165: 2147-2155.CrossRefPubMedPubMedCentral

23.

Shapira M, Ben-Izhak O, Bishara B, Futerman B, Minkov I, Krausz MM, Pagano M, Hershko DD: Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma. Cancer. 2004, 100: 1615-1621. 10.1002/cncr.20172.CrossRefPubMed

24.

Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Hershko DD: The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005, 103: 1336-1346. 10.1002/cncr.20917.CrossRefPubMed

Title: The expression of the ubiquitin ligase subunit Cks1 in human breast cancer
Authors: Merav Slotky
Ma'anit Shapira
Ofer Ben-Izhak
Shai Linn
Boris Futerman
Medy Tsalic
Dan D Hershko
Publication date: 01-10-2005
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 5/2005
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr1278

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Abstract

Introduction

Methods

Results

Conclusion

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