Abstract
Background
Cyclin-dependent kinase 10 (CDK10) has recently been identified as a tumor suppressor and, concordantly, its encoding gene has frequently been found to be inactivated in various human cancers. Here, we examined the expression status of CDK10 in a panel of primary human breast cancers and evaluated its correlation with clinicopathological parameters and clinical outcome.
Methods
Western blotting was used to assess CDK10 protein levels in 20 paired breast cancer tissues and adjacent noncancerous tissues. In addition, immunohistochemistry was performed in 128 formalin-fixed, paraffin-embedded tumor tissues. Associations of CDK10 expression with various clinicopathological parameters were evaluated and Kaplan-Meier survival analyses and Cox proportional hazards models were used to estimate its effect on patient survival.
Results
We found that CDK10 protein expression was markedly decreased in cancer tissues compared to adjacent noncancerous tissues. Immunohistochemistry revealed decreased CDK10 levels in 65/128 (50.8 %) of the primary breast cancer tissues tested. These decreased levels were found to be significantly associated with lymph node metastasis (P = 0.003), advanced tumor stage (P < 0.001) and unfavorable overall survival (P < 0.001). Furthermore, multivariate analyses indicated that CDK10 expression may serve as an independent prognostic factor for survival (P = 0.001).
Conclusion
Down-regulated CDK10 expression frequently occurs in breast cancers and correlates with disease progression and poor survival. CDK10 may serve as a prognostic biomarker for breast cancer.
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References
L.A. Torre, F. Bray, R.L. Siegel, J. Ferlay, J. Lortet-Tieulent, A. Jemal, Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015)
C.M. Perou, T. Sørlie, M.B. Eisen, M. van de Rijn, S.S. Jeffrey, C.A. Rees, J.R. Pollack, D.T. Ross, H. Johnsen, L.A. Akslen, O. Fluge, A. Pergamenschikov, C. Williams, S.X. Zhu, P.E. Lønning, A.L. Børresen-Dale, P.O. Brown, D. Botstein, Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)
S. Di Cosimo, J. Baselga, Management of breast cancer with targeted agents: importance of heterogeneity. Nat. Rev. Clin. Oncol. 7, 139–147 (2010)
J. Peppercorn, C.M. Perou, L.A. Carey, Molecular subtypes in breast cancer evaluation and management: divide and conquer. Cancer Investig. 26, 1–10 (2008)
S. Tabarestani, S.M. Ghaderian, H. Rezvani, R. Mirfakhraie, A. Ebrahimi, H. Attarian, J. Rafat, M. Ghadyani, H.A. Alavi, N. Kamalian, A. Rakhsha, E. Azargashb, Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification. Cell. Oncol. 37, 107–118 (2014)
A.H. Verschuur-Maes, C.B. Moelans, P.C. de Bruin, P.J. van Diest, Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnarcell lesions of the breast. Cell. Oncol. 37(147–154) (2014)
E. Yiannakopoulou, Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications. Cell. Oncol. 37(1–8) (2014)
L.J. van’t Veer, H. Dai, M.J. van de Vijver, Y.D. He, A.A. Hart, M. Mao, H.L. Peterse, K. van der Kooy, M.J. Marton, A.T. Witteveen, G.J. Schreiber, R.M. Kerkhoven, C. Roberts, P.S. Linsley, R. Bernards, S.H. Friend, Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002)
Cancer Genome Atlas Network, Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)
E.A. Musgrove, R.L. Sutherland, Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631–643 (2009)
C.A. Hudis, Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007)
F. Bullrich, T.K. MacLachlan, N. Sang, T. Druck, M.L. Veronese, S.L. Allen, N. Chiorazzi, A. Koff, K. Heubner, C.M. Croce et al., Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer. Cancer Res. 55, 1199–1205 (1995)
J. Crawford, L. Ianzano, M. Savino, S. Whitmore, A.M. Cleton-Jansen, C. Settasatian, M. D’apolito, R. Seshadri, J.C. Pronk, A.D. Auerbach, P.C. Verlander, C.G. Mathew, A.J. Tipping, N.A. Doggett, L. Zelante, D.F. Callen, A. Savoia, The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer. Genomics 56, 90–97 (1999)
E. Iorns, N.C. Turner, R. Elliott, N. Syed, O. Garrone, M. Gasco, A.N. Tutt, T. Crook, C.J. Lord, A. Ashworth, Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 13, 91–104 (2008)
C.J. Lord, E. Iorns, A. Ashworth, Dissecting resistance to endocrine therapy in breast cancer. Cell Cycle 7, 1895–1898 (2008)
P. Khanal, H.J. Yun, S.C. Lim, S.G. Ahn, H.E. Yoon, K.W. Kang, R. Hong, H.S. Choi, Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells. Oncogene 31, 3845–3856 (2012)
C.W. Yeh, S.H. Kao, Y.C. Cheng, L.S. Hsu, Knockdown of cyclin-dependent kinase 10 (cdk10) gene impairs neural progenitor survival via modulation of raf1a gene expression. J. Biol. Chem. 288, 27927–27939 (2013)
J.H. Yu, X.Y. Zhong, W.G. Zhang, Z.D. Wang, Q. Dong, S. Tai, H. Li, Y.F. Cui, CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells. Oncol. Rep. 27, 1266–1276 (2012)
X.Y. Zhong, X.X. Xu, J.H. Yu, G.X. Jiang, Y. Yu, S. Tai, Z.D. Wang, Y.F. Cui, Clinical and biological significance of Cdk10 in hepatocellular carcinoma. Gene 498, 68–74 (2012)
Y. You, W. Yang, Z. Wang, H. Zhu, H. Li, C. Lin, Y. Ran, Promoter hypermethylation contributes to the frequent suppression of the CDK10 gene in human nasopharyngeal carcinomas. Cell. Oncol. 36, 323–331 (2013)
C.Q. Hong, F. Zhang, Y.J. You, W.L. Qiu, A.E. Giuliano, X.J. Cui, G.J. Zhang, Y.K. Cui, Elevated C1orf63 expression is correlated with CDK10 and predicts better outcome for advanced breast cancers: a retrospective study. BMC Cancer 15, 548 (2015)
Y. You, W. Yang, X. Qin, F. Wang, H. Li, C. Lin, W. Li, C. Gu, Y. Zhang, Y. Ran, ECRG4 acts as a tumor suppressor and as a determinant of chemotherapy resistance in human nasopharyngeal carcinoma. Cell. Oncol. 38, 205–14 (2015)
A.S. Howell, D.J. Lew, Morphogenesis and the cell cycle. Genetics 190(1), 51–77 (2012)
S. Mahale, S.B. Bharate, S. Manda, P. Joshi, P.R. Jenkins, R.A. Vishwakarma, B. Chaudhuri, Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization. Cell Death Dis. 6, e1743 (2015)
T. VanArsdale, C. Boshoff, K.T. Arndt, R.T. Abraham, Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin. Cancer Res. 21, 2905–2910 (2015)
Z. Feng, S. Xu, M. Liu, Y.X. Zeng, T. Kang, Chk1 inhibitor Gö6976 enhances the sensitivity of nasopharyngeal carcinoma cells to radiotherapy and chemotherapy in vitro and in vivo. Cancer Lett. 297, 190–197 (2010)
V.J. Guen, C. Gamble, M. Flajolet, S. Unger, A. Thollet, Y. Ferandin, A. Superti-Furga, P.A. Cohen, L. Meijer, P. Colas, CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. Proc. Natl. Acad. Sci. U. S. A. 110, 19525–19530 (2013)
G. Heller, B. Ziegler, A. Brandstetter, S. Novak, M. Rudas, G. Hennig, M. Gehrmann, T. Acht, S. Zöchbauer-Müller, M. Filipits, CDK10 is not a target for aberrant DNA methylation in breast cancer. Anticancer Res. 29, 3939–3944 (2009)
A. Dhasarathy, M. Kajita, P.A. Wade, The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol. Endocrinol. 21, 2907–2918 (2007)
Y. Ran, S. Wu, Y. You, Demethylation of E-cadherin gene in nasopharyngeal carcinoma could serve as a potential therapeutic strategy. J. Biochem. 149, 49–54 (2011)
Acknowledgments
This work was supported in part by the Science and Technology Planning Project of Henan Province, China (142102310464), the Key Research Foundation of Higher Education of Henan Province, China (15B320003), the Annual Natural Science Foundation of Luohe Medical College (2015-S-LMC02), the Natural Science Foundation of Hubei Province (2014CFC1154), the Foundation of Medical College of Hubei University of Arts and Science (YXKY 201402) and the Scientific Research Foundation for Doctoral Program of Hubei University of Arts and Science (X. Qin).
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Yanjie You and Haijun Li are co-first authors for this manuscript. These authors have contributed equally to this work.
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You, Y., Li, H., Qin, X. et al. Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report. Cell Oncol. 38, 485–491 (2015). https://doi.org/10.1007/s13402-015-0246-4
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DOI: https://doi.org/10.1007/s13402-015-0246-4