Research Article
CDK2 Geninin CRISPR-CAS9 ile Hedeflenmesi 3B Luminal Meme Kanseri Modellerinde Tümöral Büyümeyi Baskılar
Abstract
Amaç: Siklin-Bağımlı Kinaz 2 (CDK2), G1/S geçişi ve genomik stabilitenin önemli bir düzenleyicisidir. Son çalışmalar, hormon reseptörü pozitif meme kanserinde CDK2 aktivitesini tedavi direnciyle ilişkilendirse de, tümörle ilişkili koşullarda fonksiyonel rolü net değildir. Bu çalışmanın amacı, luminal meme kanseri modellerinde CDK2’ye özgü bağlama-bağımlı gerekliliği ortaya koymaktır.
Gereç ve Yöntemler: CDK2, CRISPR-Cas9 sistemi kullanılarak T47D hücrelerinde devre dışı bırakıldı. Fenotipik etkiler hem 2D monolayer hem de 3D sferoid kültür modellerinde değerlendirildi. Gen silinmesi kantitatif PCR ile doğrulandı. 2D proliferasyon kolon oluşumu ve GFP-temelli rekabet analizleriyle incelendi. 3D sferoid boyutları ImageJ ile ölçüldü.
Bulgular: CDK2 silinmesi, 2D kolon oluşumunda yaklaşık %40, 3D sferoid boyutunda ise yaklaşık %50 oranında azalmaya neden oldu. Özellikle 3D ortamda CDK2’ye olan bağımlılık daha belirgin hale geldi.
Sonuç: CDK2, özellikle tümör mikroçevresini taklit eden 3D yapılarda tümöral büyüme ve yapısal bütünlüğün korunmasında kritik rol oynamaktadır. Bulgular, CDK2’nin luminal meme kanserinde, özellikle anti-östrojen direnci bağlamında potansiyel bir terapötik hedef olabileceğini göstermektedir.
Ethical Statement
We confirm that our study does not involve research conducted on either animals or humans. Therefore, ethical approval was not required. Please do not hesitate to contact me should you need any further information.
Project Number
na
References
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- Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, et al. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells. Br J Cancer 2010;102(2):342-50. google scholar
- Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene 2010;29(28). google scholar
- Caldon CE, Sergio CM, Kang J, Muthukaruppan A, Boersma MN, Stone A, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther 2012;11(7). google scholar
- Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 2005. google scholar
- Akli S, Van Pelt CS, Bui T, Meijer L, Keyomarsi K. Cdk2 is required for breast cancer mediated by the low-molecular-weight isoform of cyclin E. Cancer Res 2011;71(9):3377-86. google scholar
- Caruso JA, Duong MT, Carey JPW, Hunt KK, Keyomarsi K. Low-molecular-weight cyclin E in human cancer: Cellular consequences and opportunities for targeted therapies. Vol. 78, Cancer Research. American Association for Cancer Research Inc.; 2018. p. 5481-91. google scholar
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- Harper JW, Elledge SJ. Cdk inhibitors in development and cancer. Curr Opin Genet Dev 1996;6(1). google scholar
- Li Y, Zhang J, Gao W, Zhang L, Pan Y, Zhang S, et al. Insights on structural characteristics and ligand binding mechanisms of CDK2. Int J Mol Sci 2015;16. google scholar
- Floquet N, Costa MGS, Batista PR, Renault P, Bisch PM, Raussin F, et al. Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes. Biophys J 2015;109(6). google scholar
- Lashen A, Alqahtani S, Shoqafi A, Algethami M, Jeyapalan JN, Mongan NP, et al. Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers. Int J Mol Sci 2024;25(9). google scholar
- Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, et al. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci MDPI AG; 2020;21. google scholar
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- Pandey K, Park N, Park KS, Hur J, Cho Y Bin, Kang M, et al. Combined cdk2 and cdk4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers (Basel) 2020;12(12). google scholar
- Al-Qasem AJ, Alves CL, Ehmsen S, Tuttolomondo M, Terp MG, Johansen LE, et al. Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ Precis oncol 2022;6(1). google scholar
CDK2 Depletion Impairs Tumour Growth in the 3D Luminal Breast Cancer Model via CRISPR-CAS9 Gene Editing
Abstract
Objective: Cyclin-Dependent Kinase 2 (CDK2) is a key regulator of the G1/S transition and genomic stability. While recent studies have linked CDK2 activity to therapy resistance in hormone receptor-positive breast cancer, its functional role under tumourrelevant conditions remains unclear. This study aims to elucidate the context-specific requirement of CDK2 in luminal breast cancer models.
Material and Methods: CDK2 was knocked out in T47D cells using CRISPR-Cas9. Phenotypic effects were evaluated in both 2D monolayer and 3D spheroid cultures. Quantitative PCR validated gene knockout. Colony formation and GFP-based competition assays assessed 2D proliferation, while 3D spheroid size was quantified using ImageJ.
Results: CDK2 depletion resulted in a 40% reduction in 2D colony formation and a 50% decrease in spheroid size. The fitness disadvantage was more pronounced in 3D cultures, suggesting increased dependency on CDK2 in complex microenvironments.
Conclusion: CDK2 plays a critical role in sustaining tumour growth and structural organization, particularly in 3D environments that mimic the tumour microenvironment. These findings highlight CDK2 as a potential therapeutic target in luminal breast cancer, especially in the context of anti-oestrogen resistance.
Keywords
Ethical Statement
We confirm that our study does not involve research conducted on either animals or humans. Therefore, ethical approval was not required. Please do not hesitate to contact me should you need any further information.
Project Number
na
References
- Morgan DO. Cyclin-Dependent Kinases: Engines, Clocks, and Microprocessors. Annu Rev Cell Dev Biol 1997;13. google scholar
- Chu C, Geng Y, Zhou Y, Sicinski P. Cyclin E in normal physiology and disease states. Trends in Cell Biology 2021;31. google scholar
- Duronio RJ, Xiong Y. Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol 2013;5(3). google scholar
- Ghafouri-Fard S, Khoshbakht T, Hussen BM, Dong P, Gassler N, Taheri M, et al. A review on the role of cyclin dependent kinases in cancers., Cancer Cell International. BioMed Central Ltd; 2022;22. google scholar
- Fagundes R, Teixeira LK. Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability. Frontiers in Cell and Developmental Biology 2021;9. google scholar
- Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. Cyclin E-CDK2 is a regulator of p27 Kip1. 1997. google scholar
- Chuang LC, Teixeira LK, Wohlschlegel JA, Henze M, Yates JR, Mendez J, et al. Phosphorylation of Mcm2 by Cdc7 Promotes Pre-replication Complex Assembly during Cell-Cycle Re-entry. Mol Cell 2009;35(2):206-16. google scholar
- Bastians H, Townsley FM, Ruderman JV. The cyclin-dependent kinase inhibitor p27Kip1 induces N-terminal proteolytic cleavage of cyclin A. Proc Natl Acad Sci U S A 1998;95(26). google scholar
- Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Vol. 14, Nature Reviews Drug Discovery. Nature Publishing Group; 2015. p. 130-46. google scholar
- Wang H, Liu YC, Zhu CY, Yan F, Wang MZ, Chen XS, et al. Chidamide increases the sensitivity of refractory or relapsed acute myeloid leukemia cells to anthracyclines via regulation of the HDAC3 -AKT-P21-CDK2 signaling pathway. J Experim Clin Cancer Res 2020;39(1):278. google scholar
- Zhang X, Pan Y, Fu H, Zhang J. Nucleolar and spindle associated protein 1 (NUSAP1) inhibits cell proliferation and enhances susceptibility to epirubicin in invasive breast cancer cells by regulating cyclin D kinase (CDK1) and DLGAP5 expression. Medical Science Monitor 2018;24. google scholar
- Aruge S, Asif M, Tariq A, Asif S, Zafar M, Elahi MA, et al. Impact of MTHFD2 Expression in Bladder/Breast Cancer and Screening of Its Potential Inhibitor. ACS Omega 2024;9(44):44193-202. google scholar
- Liu F, Liu Y, He C, Tao L, He X, Song H, et al. Increased MTHFD2 expression is associated with poor prognosis in breast cancer. Tumor Biology 2014;35(9):8685-90. google scholar
- Pardo-Lorente N, Sdelci S. MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions. NPJ Metabolic Health and Disease 2024;2(1):3. google scholar
- Nie L, Wei Y, Zhang F, Hsu YH, Chan LC, Xia W, et al. CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. Nat Commun 2019;10(1). google scholar
- Yang CC, Labaff A, Wei Y, Nie L, Xia W, Huo L, et al. Phosphorylation of EZH2 at T416 by CDK2 contributes to the malignancy of triple negative breast cancers. Am J Transl Res 2015;7. google scholar
- Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11(5). google scholar
- Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, et al. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells. Br J Cancer 2010;102(2):342-50. google scholar
- Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene 2010;29(28). google scholar
- Caldon CE, Sergio CM, Kang J, Muthukaruppan A, Boersma MN, Stone A, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther 2012;11(7). google scholar
- Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 2005. google scholar
- Akli S, Van Pelt CS, Bui T, Meijer L, Keyomarsi K. Cdk2 is required for breast cancer mediated by the low-molecular-weight isoform of cyclin E. Cancer Res 2011;71(9):3377-86. google scholar
- Caruso JA, Duong MT, Carey JPW, Hunt KK, Keyomarsi K. Low-molecular-weight cyclin E in human cancer: Cellular consequences and opportunities for targeted therapies. Vol. 78, Cancer Research. American Association for Cancer Research Inc.; 2018. p. 5481-91. google scholar
- Han K, Pierce SE, Li A, Spees K, Anderson GR, Seoane JA, et al. CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities. Nature 2020;580(7801). google scholar
- Bloise N, Giannaccari M, Guagliano G, Peluso E, Restivo E, Strada S, et al. Growing Role of 3D In Vitro Cell Cultures in the Study of Cellular and Molecular Mechanisms: Short Focus on Breast Cancer, Endometriosis, Liver and Infectious Diseases. Vol. 13, Cells. Multidisciplinary Digital Publishing Institute (MDPI); 2024. google scholar
- Barbosa MAG, Xavier CPR, Pereira RF, Petrikaite V, Vasconcelos MH. 3D Cell Culture Models as Recapitulators of the Tumor Microenvironment for the Screening of Anti-Cancer Drugs. Cancers 2022;14. google scholar
- Habanjar O, Diab-Assaf M, Caldefie-Chezet F, Delort L. 3D cell culture systems: Tumor application, advantages, and disadvantages. Int J Mol Sci 2021;22. google scholar
- Kapatczynska M, Kolenda T, Przybyta W, Zajşczkowska M, Teresiak A, Filas V, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci 2018;14(4). google scholar
- Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 2014;11(8):783-4. google scholar
- Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science (1979) 2014;343(6166). google scholar
- Harper JW, Elledge SJ. Cdk inhibitors in development and cancer. Curr Opin Genet Dev 1996;6(1). google scholar
- Li Y, Zhang J, Gao W, Zhang L, Pan Y, Zhang S, et al. Insights on structural characteristics and ligand binding mechanisms of CDK2. Int J Mol Sci 2015;16. google scholar
- Floquet N, Costa MGS, Batista PR, Renault P, Bisch PM, Raussin F, et al. Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes. Biophys J 2015;109(6). google scholar
- Lashen A, Alqahtani S, Shoqafi A, Algethami M, Jeyapalan JN, Mongan NP, et al. Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers. Int J Mol Sci 2024;25(9). google scholar
- Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, et al. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci MDPI AG; 2020;21. google scholar
- Jensen C, Teng Y. Is It Time to Start Transitioning From 2D to 3D Cell Culture? Vol. 7, Frontiers in Molecular Biosciences. Frontiers Media S.A.; 2020. google scholar
- Urzî o, Gasparro R, Costanzo E, De Luca a, Giavaresi G, Fontana S, et al, Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models. Int J Mol Sci, Multidisciplinary Digital Publishing Institute (MDPI); 2023;24, google scholar
- Zhang C, Wang X, Zhang C, Icaritin inhibits CDK2 expression and activity to interfere with tumor progression, iScience 2022;25(9), google scholar
- Bacevic K, Lossaint G, Achour TN, Georget V, Fisher D, Dulic V. Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage, Sci Rep 2017;7(1). google scholar
- Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: Several cdks, numerous cyclins and diverse compensatory mechanisms. oncogene 2009;28:2925-39. google scholar
- Satyanarayana A, Kaldis P. A dual role of Cdk2 in DNA damage response. Cell Division 2009;4. google scholar
- Morrison E, Wai P, Leonidou A, Bland P, Khalique S, Farnie G, et al. Utilizing functional genomics screening to identify potentially novel drug targets in cancer cell spheroid cultures. J Visualized Experiments 2016;2016(118). google scholar
- He X, Xiang H, Zong X, Yan X, Yu Y, Liu G, et al. CDK2-AP1 inhibits growth of breast cancer cells by regulating cell cycle and increasing docetaxel sensitivity in vivo and in vitro. Cancer Cell Int 2014;14(1). google scholar
- Pandey K, Park N, Park KS, Hur J, Cho Y Bin, Kang M, et al. Combined cdk2 and cdk4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers (Basel) 2020;12(12). google scholar
- Al-Qasem AJ, Alves CL, Ehmsen S, Tuttolomondo M, Terp MG, Johansen LE, et al. Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ Precis oncol 2022;6(1). google scholar
There are 45 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences (Other) |
| Journal Section | Research Article |
| Authors | |
| Project Number | na |
| Publication Date | June 30, 2025 |
| Submission Date | April 11, 2025 |
| Acceptance Date | June 4, 2025 |
| Published in Issue | Year 2025 |