Skip to main content
Top
Published in: Cellular Oncology 6/2015

01-12-2015 | Original Paper

Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report

Authors: Yanjie You, Haijun Li, Xin Qin, Yinpo Zhang, Wengang Song, Yonggang Ran, Fenglan Gao

Published in: Cellular Oncology | Issue 6/2015

Login to get access

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.
Literature
1.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
2.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
3.
go back to reference S. Di Cosimo, J. Baselga, Management of breast cancer with targeted agents: importance of heterogeneity. Nat. Rev. Clin. Oncol. 7, 139–147 (2010)CrossRefPubMed S. Di Cosimo, J. Baselga, Management of breast cancer with targeted agents: importance of heterogeneity. Nat. Rev. Clin. Oncol. 7, 139–147 (2010)CrossRefPubMed
4.
go back to reference 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)CrossRef 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)CrossRef
5.
go back to reference 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) 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)
6.
go back to reference 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) 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)
7.
go back to reference E. Yiannakopoulou, Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications. Cell. Oncol. 37(1–8) (2014) E. Yiannakopoulou, Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications. Cell. Oncol. 37(1–8) (2014)
8.
go back to reference 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)CrossRef 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)CrossRef
9.
go back to reference Cancer Genome Atlas Network, Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)CrossRef Cancer Genome Atlas Network, Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)CrossRef
10.
go back to reference E.A. Musgrove, R.L. Sutherland, Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631–643 (2009)CrossRefPubMed E.A. Musgrove, R.L. Sutherland, Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631–643 (2009)CrossRefPubMed
11.
go back to reference C.A. Hudis, Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007)CrossRefPubMed C.A. Hudis, Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007)CrossRefPubMed
12.
go back to reference 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)PubMed 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)PubMed
13.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
14.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
15.
go back to reference C.J. Lord, E. Iorns, A. Ashworth, Dissecting resistance to endocrine therapy in breast cancer. Cell Cycle 7, 1895–1898 (2008)CrossRefPubMed C.J. Lord, E. Iorns, A. Ashworth, Dissecting resistance to endocrine therapy in breast cancer. Cell Cycle 7, 1895–1898 (2008)CrossRefPubMed
16.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
17.
go back to reference 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)PubMedCentralCrossRefPubMed 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)PubMedCentralCrossRefPubMed
18.
go back to reference 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)PubMedCentralPubMed 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)PubMedCentralPubMed
19.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
20.
go back to reference 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)CrossRef 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)CrossRef
21.
go back to reference 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)PubMedCentralCrossRefPubMed 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)PubMedCentralCrossRefPubMed
22.
go back to reference 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)CrossRef 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)CrossRef
24.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
25.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
26.
go back to reference 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)CrossRefPubMed 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)CrossRefPubMed
27.
go back to reference 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)PubMedCentralCrossRefPubMed 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)PubMedCentralCrossRefPubMed
28.
go back to reference 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)PubMed 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)PubMed
29.
go back to reference 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)PubMedCentralCrossRefPubMed 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)PubMedCentralCrossRefPubMed
30.
go back to reference 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) 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)
Metadata
Title
Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report
Authors
Yanjie You
Haijun Li
Xin Qin
Yinpo Zhang
Wengang Song
Yonggang Ran
Fenglan Gao
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 6/2015
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-015-0246-4

Other articles of this Issue 6/2015

Cellular Oncology 6/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine