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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling

Author(s): Fang Peng, Chuansheng Yang, Yanan Kong, Xiaojia Huang, Yanyu Chen, Yangfan Zhou, Xinhua Xie* and Peng Liu*

Volume 20, Issue 2, 2020

Page: [156 - 165] Pages: 10

DOI: 10.2174/1568009619666191118113220

Price: $65


Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness.

Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness.

Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway.

Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis.

Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

Keywords: Breast cancer, stemness, metastasis, CDK12, c-myc, β-catenin.

Graphical Abstract
Lytle, N.K.; Barber, A.G.; Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer, 2018, 18(11), 669-680.
[] [PMID: 30228301]
Tang, H.; Chen, B.; Liu, P.; Xie, X.; He, R.; Zhang, L.; Huang, X.; Xiao, X.; Xie, X. SOX8 acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer. Carcinogenesis, 2019, 40(10), 1278-1287.
[] [PMID: 30810729]
Tang, H.; Huang, X.; Wang, J.; Yang, L.; Kong, Y.; Gao, G.; Zhang, L.; Chen, Z.S.; Xie, X. circKIF4A acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer. Mol. Cancer, 2019, 18(1), 23.
[] [PMID: 30744636]
Ekumi, K.M.; Paculova, H.; Lenasi, T.; Pospichalova, V.; Bösken, C.A.; Rybarikova, J.; Bryja, V.; Geyer, M.; Blazek, D.; Barboric, M. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Res., 2015, 43(5), 2575-2589.
[] [PMID: 25712099]
Wu, Y.M.; Cieslik, M.; Lonigro, R.J.; Vats, P.; Reimers, M.A.; Cao, X.; Ning, Y.; Wang, L.; Kunju, L.P.; de Sarkar, N.; Heath, E.I.; Chou, J.; Feng, F.Y.; Nelson, P.S.; de Bono, J.S.; Zou, W.; Montgomery, B.; Alva, A.; Robinson, D.R.; Chinnaiyan, A.M. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer Cell,, 2018, 173(2018) 1770- 1782.e1714.
Blazek, D.; Kohoutek, J.; Bartholomeeusen, K.; Johansen, E.; Hulinkova, P.; Luo, Z.; Cimermancic, P.; Ule, J.; Peterlin, B.M. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev., 2011, 25(20), 2158-2172.
[] [PMID: 22012619]
Chen, H.H.; Wang, Y.C.; Fann, M.J. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol. Cell. Biol., 2006, 26(7), 2736-2745.
[] [PMID: 16537916]
Davidson, L.; Muniz, L.; West, S. 3′ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. Genes Dev., 2014, 28(4), 342-356.
[] [PMID: 24478330]
Eifler, T.T.; Shao, W.; Bartholomeeusen, K.; Fujinaga, K.; Jäger, S.; Johnson, J.R.; Luo, Z.; Krogan, N.J.; Peterlin, B.M. Cyclin-dependent kinase 12 increases 3′ end processing of growth factor-induced c-FOS transcripts. Mol. Cell. Biol., 2015, 35(2), 468-478.
[] [PMID: 25384976]
Krajewska, M.; Dries, R.; Grassetti, A.V.; Dust, S.; Gao, Y.; Huang, H.; Sharma, B.; Day, D.S.; Kwiatkowski, N.; Pomaville, M.; Dodd, O.; Chipumuro, E.; Zhang, T.; Greenleaf, A.L.; Yuan, G.C.; Gray, N.S.; Young, R.A.; Geyer, M.; Gerber, S.A.; George, R.E. CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation. Nat. Commun., 2019, 10(1), 1757.
[] [PMID: 30988284]
Naidoo, K.; Wai, P.T.; Maguire, S.L.; Daley, F.; Haider, S.; Kriplani, D.; Campbell, J.; Mirza, H.; Grigoriadis, A.; Tutt, A.; Moseley, P.M.; Abdel-Fatah, T.M.A.; Chan, S.Y.T.; Madhusudan, S.; Rhaka, E.A.; Ellis, I.O.; Lord, C.J.; Yuan, Y.; Green, A.R.; Natrajan, R. Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response-targeted therapies in breast cancer. Mol. Cancer Ther., 2018, 17(1), 306-315.
[] [PMID: 29133620]
Johnson, S.F.; Cruz, C.; Greifenberg, A.K.; Dust, S.; Stover, D.G.; Chi, D.; Primack, B.; Cao, S.; Bernhardy, A.J.; Coulson, R.; Lazaro, J.B.; Kochupurakkal, B.; Sun, H.; Unitt, C.; Moreau, L.A.; Sarosiek, K.A.; Scaltriti, M.; Juric, D.; Baselga, J.; Richardson, A.L.; Rodig, S.J.; D’Andrea, A.D.; Balmaña, J.; Johnson, N.; Geyer, M.; Serra, V.; Lim, E.; Shapiro, G.I. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep., 2016, 17(9), 2367-2381.
[] [PMID: 27880910]
Bartkowiak, B.; Liu, P.; Phatnani, H.P.; Fuda, N.J.; Cooper, J.J.; Price, D.H.; Adelman, K.; Lis, J.T.; Greenleaf, A.L. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev., 2010, 24(20), 2303-2316.
[] [PMID: 20952539]
Tien, J.F.; Mazloomian, A.; Cheng, S.G.; Hughes, C.S.; Chow, C.C.T.; Canapi, L.T.; Oloumi, A.; Trigo-Gonzalez, G.; Bashashati, A.; Xu, J.; Chang, V.C.; Shah, S.P.; Aparicio, S.; Morin, G.B. CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion. Nucleic Acids Res., 2017, 45(11), 6698-6716.
[] [PMID: 28334900]
Cowling, V.H.; D’Cruz, C.M.; Chodosh, L.A.; Cole, M.D. c-Myc transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol. Cell. Biol., 2007, 27(14), 5135-5146.
[] [PMID: 17485441]
Deming, S.L.; Nass, S.J.; Dickson, R.B.; Trock, B.J. C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br. J. Cancer, 2000, 83(12), 1688-1695.
[] [PMID: 11104567]
Zeng, Y.A.; Nusse, R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell, 2010, 6(6), 568-577.
[] [PMID: 20569694]
Teissedre, B.; Pinderhughes, A.; Incassati, A.; Hatsell, S.J.; Hiremath, M.; Cowin, P. MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors. PLoS One, 2009, 4(2)e4537
[] [PMID: 19225568]
Li, Y.; Welm, B.; Podsypanina, K.; Huang, S.; Chamorro, M.; Zhang, X.; Rowlands, T.; Egeblad, M.; Cowin, P.; Werb, Z.; Tan, L.K.; Rosen, J.M.; Varmus, H.E. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl. Acad. Sci. USA, 2003, 100(26), 15853-15858.
[] [PMID: 14668450]
Incassati, A.; Chandramouli, A.; Eelkema, R.; Cowin, P. Key signaling nodes in mammary gland development and cancer: β-catenin. Breast Cancer Res., 2010, 12(6), 213.
[] [PMID: 21067528]
Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature, 2001, 414(6859), 105-111.
[] [PMID: 11689955]
Visvader, J.E.; Lindeman, G.J. Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 2012, 10(6), 717-728.
[] [PMID: 22704512]
Trimboli, A.J.; Fukino, K.; de Bruin, A.; Wei, G.; Shen, L.; Tanner, S.M.; Creasap, N.; Rosol, T.J.; Robinson, M.L.; Eng, C.; Ostrowski, M.C.; Leone, G. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res., 2008, 68(3), 937-945.
[] [PMID: 18245497]
Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer, 2002, 2(6), 442-454.
[] [PMID: 12189386]
Wu, Y.; Zhou, B.P. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim. Biophys. Sin. (Shanghai), 2008, 40(7), 643-650.
[] [PMID: 18604456]
Huber, M.A.; Kraut, N.; Beug, H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol., 2005, 17(5), 548-558.
[] [PMID: 16098727]

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