La expresión alterada de tirosina quinasa de treonina (TTK) se asocia con resultados clínicos adversos en tumores de mama: Un enfoque in silico

Autores/as

DOI:

https://doi.org/10.33448/rsd-v12i13.44285

Palabras clave:

Biomarcadores; Neoplasias de la Mama; Biología computacional.

Resumen

La neoplasia maligna más incidente y letal en mujeres a nivel global sigue siendo la de mama. Se ha demostrado que  tirosina quinasa de treonina (TTK) es una molécula crítica en el punto de control de ensamblaje del huso mitótico (SAC), lo que resulta en una correcta segregación cromosómica y mantenimiento de la estabilidad genómica. Por lo tanto, el presente estudio se realizó para evaluar el patrón de expresión del tirosina quinasa de treonina (TTK) en el cáncer de mama y su potencial valor pronóstico y predictivo para la respuesta terapéutica utilizando herramientas de bioinformática. Se seleccionaron plataformas web que contienen información clínica y datos de microarreglos de cDNA para realizar análisis in silico del potencial marcador tirosina quinasa de treonina (TTK). Se descubrió que el gen tirosina quinasa de treonina (TTK) se expresa diferencialmente en muestras tumorales en comparación con muestras de tejido mamario sano (p<0.0001), y el subtipo TNBC exhibió la expresión más alta de tirosina quinasa de treonina (TTK) en comparación con otros subtipos (p<0.0001). Además, las curvas de Kaplan-Meier revelaron que niveles altos de tirosina quinasa de treonina (TTK) correspondieron a un resultado desfavorable para la supervivencia global (p<0.0001), así como para la supervivencia libre de recurrencia (p<0.0001) y la supervivencia libre de metástasis distante (p<0.0001). Por último, la expresión diferencial de tirosina quinasa de treonina (TTK) se relacionó con la respuesta de pacientes con cáncer de mama a diferentes terapias. Nuestros resultados acumulativos demuestran que tirosina quinasa de treonina (TTK) puede ser un biomarcador prometedor para predecir el pronóstico y la respuesta terapéutica en pacientes con cáncer de mama.

Citas

Afzal, S., Hassan, M., Ullah, S., Abbas, H., Tawakkal, F., & Khan, M. A. (2022). Breast Cancer; Discovery of Novel Diagnostic Biomarkers, Drug Resistance, and Therapeutic Implications. Frontiers in Molecular Biosciences, 9(2), 1–10. https://doi.org/10.3389/fmolb.2022.783450

Albogami, S. (2022). Comprehensive analysis of gene expression profiles to identify differential prognostic factors of primary and metastatic breast cancer. Saudi Journal of Biological Sciences, 29(7), 1–18. https://doi.org/10.1016/j.sjbs.2022.103318

Anderhub, S. J., Mak, G. W. Y., Gurden, M. D., Faisal, A., Drosopoulos, K., Walsh, K., Woodward, H. L., Innocenti, P., Westwood, I. M., Naud, S., Hayes, A., Theofani, E., Filosto, S., Saville, H., Burke, R., van Montfort, R. L. M., Raynaud, F. I., Blagg, J., Hoelder, S., & Linardopoulos, S. (2019). High proliferation rate and a compromised spindle assembly checkpoint confers sensitivity to the MPS1 inhibitor BOS172722 in triple-negative breast cancers. Molecular Cancer Therapeutics, 18(10), 1696–1707. https://doi.org/10.1158/1535-7163.MCT-18-1203

Bhushan, A., Gonsalves, A., & Menon, J. U. (2021). Current state of breast cancer diagnosis, treatment, and theranostics. Pharmaceutics, 13(5), 1–24. https://doi.org/10.3390/pharmaceutics13050723

Chandler, B. C., Moubadder, L., Ritter, C. L., Liu, M., Cameron, M., Wilder-Romans, K., Zhang, A., Pesch, A. M., Michmerhuizen, A. R., Hirsh, N., Androsiglio, M., Ward, T., Olsen, E., Niknafs, Y. S., Merajver, S., Thomas, D. G., Brown, P. H., Lawrence, T. S., Nyati, S., … Speers, C. (2020). TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. Journal of Clinical Investigation, 130(2), 958–973. https://doi.org/10.1172/JCI130435

Chandrashekar, D. S., Karthikeyan, S. K., Korla, P. K., Patel, H., Shovon, A. R., Athar, M., Netto, G. J., Qin, Z. S., Kumar, S., Manne, U., Crieghton, C. J., & Varambally, S. (2022). UALCAN: An update to the integrated cancer data analysis platform. Neoplasia, 25(1), 18–27. https://doi.org/10.1016/j.neo.2022.01.001

Chen, F., Wu, P., Hu, H., Tian, D., Jiang, N., & Wu, C. (2018). Protein kinase TTK promotes proliferation and migration and mediates epithelial-mesenchymal transition in human bladder cancer cells. International Journal of Clinical and Experimental Pathology, 11(10), 4854–4861. http://www.ncbi.nlm.nih.gov/pubmed/31949560%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6962905

Chen, J., Wu, R., Xuan, Y., Jiang, M., & Zeng, Y. (2020). Bioinformatics analysis and experimental validation of TTK as a biomarker for prognosis in non-small cell lung cancer. Bioscience Reports, 40(10), 1–14. https://doi.org/10.1042/BSR20202711

Combes, G., Barysz, H., Garand, C., Gama Braga, L., Alharbi, I., Thebault, P., Murakami, L., Bryne, D. P., Stankovic, S., Eyers, P. A., Bolanos-Garcia, V. M., Earnshaw, W. C., Maciejowski, J., Jallepalli, P. V., & Elowe, S. (2018). Mps1 Phosphorylates Its N-Terminal Extension to Relieve Autoinhibition and Activate the Spindle Assembly Checkpoint. Current Biology, 28(6), 872–883. https://doi.org/10.1016/j.cub.2018.02.002

Elango, R., Vishnubalaji, R., Shaath, H., & Alajez, N. M. (2021). Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel. Molecular Therapy - Methods and Clinical Development, 20(3), 601–614. https://doi.org/10.1016/j.omtm.2021.01.013

Fekete, J. T., & Győrffy, B. (2019). ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients. International Journal of Cancer, 145(11), 3140–3151. https://doi.org/10.1002/ijc.32369

Gao, Y.-H., QU, S.-S., Cao, L.-Q., & Yao, M. (2022). TTK predicts triple positive breast cancer prognosis and regulates tumor proliferation and invasion. Neoplasma, 69(2), 274–282. https://doi.org/10.4149/neo

Győrffy, B. (2023). Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer. GeroScience, 45(3), 1889–1898. https://doi.org/10.1007/s11357-023-00742-4

Gyorffy, B., Bottai, G., Lehmann-Che, J., Kéri, G., Orfi, L., Iwamoto, T., Desmedt, C., Bianchini, G., Turner, N. C., de Thè, H., André, F., Sotiriou, C., Hortobagyi, G. N., Di Leo, A., Pusztai, L., & Santarpia, L. (2014). TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers. Molecular Oncology, 8(3), 508–519. https://doi.org/10.1016/j.molonc.2013.12.018

Jézéquel, P., Gouraud, W., Ben Azzouz, F., Guérin-Charbonnel, C., Juin, P. P., Lasla, H., & Campone, M. (2021). Bc-GenExMiner 4.5: New mining module computes breast cancer differential gene expression analyses. Database, 27(3), 1–10. https://doi.org/10.1093/database/baab007

King, J. L., Zhang, B., Li, Y., Li, K. P., Ni, J. J., Saavedra, H. I., & Dong, J. T. (2018). TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer. Oncogenesis, 7(69), 1–13. https://doi.org/10.1038/s41389-018-0077-z

Kuijt, T. E. F., Lambers, M. L. A., Weterings, S., Ponsioen, B., Bolhaqueiro, A. C. F., Staijen, D. H. M., & Kops, G. J. P. L. (2020). A Biosensor for the Mitotic Kinase MPS1 Reveals Spatiotemporal Activity Dynamics and Regulation. Current Biology, 30(19), 3862–3870. https://doi.org/10.1016/j.cub.2020.07.062

Lee, M. Y., Marina, M., King, J. L., & Saavedra, H. I. (2014). Differential expression of centrosome regulators in Her2+ breast cancer cells versus non-tumorigenic MCF10A cells. Cell Division, 9(1), 1–14. https://doi.org/10.1186/1747-1028-9-3

Maia, A. R. R., De Man, J., Boon, U., Janssen, A., Song, J. Y., Omerzu, M., Sterrenburg, J. G., Prinsen, M. B. W., Willemsen-Seegers, N., De Roos, J. A. D. M., Van Doornmalen, A. M., Uitdehaag, J. C. M., Kops, G. J. P. L., Jonkers, J., Buijsman, R. C., Zaman, G. J. R., & Medema, R. H. (2015). Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model. Annals of Oncology, 26(10), 2180–2192. https://doi.org/10.1093/annonc/mdv293

Maire, V., Baldeyron, C., Richardson, M., Tesson, B., Vincent-Salomon, A., Gravier, E., Marty-Prouvost, B., De Koning, L., Rigaill, G., Dumont, A., Gentien, D., Barillot, E., Roman-Roman, S., Depil, S., Cruzalegui, F., Pierré, A., Tucker, G. C., & Dubois, T. (2013). TTK/hMPS1 Is an Attractive Therapeutic Target for Triple-Negative Breast Cancer. PLoS ONE, 8(5), 1–15. https://doi.org/10.1371/journal.pone.0063712

Mason, J. M., Wei, X., Fletcher, G. C., Kiarash, R., Brokx, R., Hodgson, R., Beletskaya, I., Bray, M. R., & Mak, T. W. (2017). Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. PNAS, 114(12), 3127–3132. https://doi.org/10.1073/pnas.1700234114

Menezo, Y., Clement, P., Clement, A., & Elder, K. (2020). Methylation: An ineluctable biochemical and physiological process essential to the transmission of life. International Journal of Molecular Sciences, 21(23), 1–13. https://doi.org/10.3390/ijms21239311

Miao, Y., Konno, Y., Wang, B., Zhu, L., Zhai, T., Ihira, K., Kobayashi, N., Watari, H., Jin, X., Yue, J., Dong, P., & Fang, M. (2023). Integrated multi-omics analyses and functional validation reveal TTK as a novel EMT activator for endometrial cancer. Journal of Translational Medicine, 21(1), 1–23. https://doi.org/10.1186/s12967-023-03998-8

Rivera-Rivera, Y., Vargas, G., Jaiswal, N., Núñez-Marrero, A., Li, J., Chen, D. T., Eschrich, S., Rosa, M., Johnson, J. O., Dutil, J., Chellappan, S. P., & Saavedra, H. I. (2022). Ethnic and racial-specific differences in levels of centrosome-associated mitotic kinases, proliferative and epithelial-to-mesenchymal markers in breast cancers. Cell Division, 17(6), 1–14. https://doi.org/10.1186/s13008-022-00082-3

Schick, J., Ritchie, R. P., & Restini, C. (2021). Breast Cancer Therapeutics and Biomarkers: Past, Present, and Future Approaches. Breast Cancer: Basic and Clinical Research, 15(3), 1–19. https://doi.org/10.1177/1178223421995854

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660

Tang, D., Zhao, X., Zhang, L., Wang, Z., & Wang, C. (2019). Identification of hub genes to regulate breast cancer metastasis to brain by bioinformatics analyses. Journal of Cellular Biochemistry, 120(6), 9522–9531. https://doi.org/10.1002/jcb.28228

Tang, J., Lu, M., Cui, Q., Zhang, D., Kong, D., Liao, X., Ren, J., Gong, Y., & Wu, G. (2019). Overexpression of ASPM, CDC20, and TTK Confer a Poorer Prognosis in Breast Cancer Identified by Gene Co-expression Network Analysis. Frontiers in Oncology, 9(4), 1–14. https://doi.org/10.3389/fonc.2019.00310

Xie, Y., Wang, A., Lin, J., Wu, L., Zhang, H., Yang, X., Wan, X., Miao, R., Sang, X., & Zhao, H. (2017). Mps1/TTK: A novel target and biomarker for cancer. Journal of Drug Targeting, 25(2), 112–118. https://doi.org/10.1080/1061186X.2016.1258568

Xu, Q., Xu, Y., Pan, B., Wu, L., Ren, X., Zhou, Y., Mao, F., Lin, Y., Guan, J., Shen, S., Zhang, X., Wang, C., Zhong, Y., Zhou, L., Liang, Z., Zhao, H., & Sun, Q. (2016). TTK is a favorable prognostic biomarker for triple-negative breast cancer survival. Oncotarget, 7(49), 81815–81829. https://doi.org/10.18632/oncotarget.13245

Zaman, G. J. R., De Roos, J. A. D. M., Libouban, M. A. A., Prinsen, M. B. W., De Man, J., Buijsman, R. C., & Uitdehaag, J. C. M. (2017). TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers. Molecular Cancer Therapeutics, 16(11), 2609–2617. https://doi.org/10.1158/1535-7163.MCT-17-0342

Zhang, X., Huang, L., Sun, J., Liu, J., & Zong, Y. (2023). Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α. Breast Cancer Research and Treatment, 202(9), 595–606. https://doi.org/10.1055/s-0037-1608898

Descargas

Publicado

27/11/2023

Cómo citar

SILVA, G. B. R. da .; CRUZ, B. S. .; VIEIRA, J. G. .; UZUM, J. M. .; NASCIMENTO, R. G. do .; PEREIRA, G. J. V. . La expresión alterada de tirosina quinasa de treonina (TTK) se asocia con resultados clínicos adversos en tumores de mama: Un enfoque in silico. Research, Society and Development, [S. l.], v. 12, n. 13, p. e40121344285, 2023. DOI: 10.33448/rsd-v12i13.44285. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/44285. Acesso em: 22 nov. 2024.

Número

Sección

Ciencias de la salud