Ekspresi Gen TP53 Pada Kanker Payudara: Implikasi Molekuler Terhadap Respon Terapi dan Pengembangan Pengobatan Presisi
DOI:
https://doi.org/10.32939/symbiotic.v6i2.217Keywords:
TP53 Gene, Breast Cancer, Mutations, Precision Therapy, Drug ResistanceAbstract
Breast cancer remains the most prevalent malignancy among women worldwide and a leading cause of cancer-related mortality. One of the critical molecular determinants in its pathogenesis is mutation of the TP53 gene, often referred to as the “guardian of the genome” due to its essential roles in cell cycle control, DNA repair, and apoptosis. This study aims to examine TP53 gene expression and mutation patterns in breast cancer and their implications for therapeutic response and precision medicine strategies. A systematic literature review was conducted following the PRISMA guidelines, sourcing articles from Scopus, PubMed, Web of Science, and DOAJ databases published between 2015 and 2024. The findings indicate that TP53 mutations occur in approximately 30% of breast cancer cases, with the highest prevalence in the triple-negative breast cancer (TNBC) subtype. Common hotspot mutations, including R175H and R248Q, result in loss of p53 tumor-suppressor function, resistance to chemotherapeutic agents such as doxorubicin and cisplatin, and activation of the PI3K/AKT pro-survival pathway. Emerging therapeutic strategies—such as p53 reactivators (e.g., APR-246), MDM2 inhibitors, immune checkpoint inhibitors, and CRISPR/Cas9-based gene editing—offer promising avenues for targeted intervention. This review underscores the importance of individualized genomic profiling to optimize breast cancer treatment, particularly in Asian populations.
Downloads
References
Acikalin Coskun, K., Tutar, M., Al, M., Gok Yurttas, A., Cansu Abay, E., Yurekli, N., Yeman Kiyak, B., Ucar Cifci, K., & Tutar, Y. (2022). Role of p53 in Human Cancers. In p53 - A Guardian of the Genome and Beyond. IntechOpen. https://doi.org/10.5772/intechopen.101961
Ahmed, Zubair, H., & Ahmad, A. (2022). Bcl-2 in cancer therapy: Targeting resistance and restoring apoptosis. Journal of Experimental & Clinical Cancer Research, 41(1), 12.
Balkrishna, A., Umar Zango, U., Kauser Nasir, S., & Arya, V. (2023). A Clinical Cognizance of Molecular and Pathological Diagnostic Approach of TNBC. In Therapeutic Drug Targets and Phytomedicine For Triple Negative Breast Cancer (pp. 26–46). BENTHAM SCIENCE PUBLISHERS. https://doi.org/10.2174/9789815079784123010005
Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G. (2020). Targeting mutant p53 for efficient cancer therapy. . Nature Reviews Cancer, 20(2), 89–102.
Chen, S. H., Tse, K. P., Lu, Y. J., Chen, S. J., Tian, Y. F., Tan, K. T., & Li, C. F. (2024). Comprehensive genomic profiling and therapeutic implications for Taiwanese patients with treatment‐naïve breast cancer. Cancer Medicine, 13(12), 1–16.
Gaowa, S., Futamura, M., Tsuneki, M., Kamino, H., Tajima, J. Y., Mori, R., & Yoshida, K. (2018). Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer. Cancer Science, 109(12), 3910–3920.
Goel, S., Bergholz, J. S., & Zhao, J. J. (2022). Targeting CDK4 and CDK6 in cancer. Nature Reviews Cancer, 22(6), 356–372. https://doi.org/10.1038/s41568-022-00456-3
Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019). The multiple mechanisms that regulate p53 activity and cell fate. Nature Reviews Molecular Cell Biology, 20(4), 199–210.
Hidayah, N., Pratiwi, R., & Putra, A. (2020). Ekspresi Relatif mRNA p53, Apaf-1 dan Survivin terkait Apoptosis serta NF-kappaB. Universitas Gadjah Mada Repository.
Hua, Z., White, J., & Zhou, J. (2022). Cancer stem cells in TNBC. Seminars in Cancer Biology, 82, 26–34. https://doi.org/10.1016/j.semcancer.2021.06.015
Huang, D., Li, Q., Sun, X., Sun, X., Tang, Y., Qu, Y., Liu, D., Yu, T., Li, G., Tong, T., & Zhang, Y. (2021). CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis. Cell Death & Differentiation, 28(5), 1593–1609. https://doi.org/10.1038/s41418-020-00689-5
Huszno, J., & Grzybowska, E. (2018). TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer (Review). Oncology Letters, 16(1), 34–40. https://doi.org/10.3892/ol.2018.8627
International Agency for Research on Cancer (IARC). (2022). Indonesia Fact Sheet - Global Cancer Observatory.
Jeyachandran, S., Chandrashekar, K., Ganesan, G., Alagarsamy, L., Subbaraj, G. K., & Kulanthaivel, L. (2022b). Triple-Negative Breast Cancer (TNBC): Clinical Features and Therapeutic Targets. In Handbook of Animal Models and its Uses in Cancer Research (pp. 1–14). Springer Nature Singapore. https://doi.org/10.1007/978-981-19-1282-5_41-1
Johnson, L., & Lee, K. (2021). MDM2 Inhibitors: A New Era in Cancer Treatment. Clinical Cancer Research, 27(4), 789–800.
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., Leiserson, M. D. M., Miller, C. A., Welch, J. S., Walter, M. J., Wendl, M. C., Ley, T. J., Wilson, R. K., Raphael, B. J., &
Ding, L. (2021). Mutational landscape and significance across 12 major cancer types. Nature, 502(7471), 333–339. https://doi.org/10.1038/nature12634
Konstantakos, V., Nteliopoulos, G., & Papalois, A. (2021). CRISPR-Cas9 technology in breast cancer research: Current applications and future perspectives. Cancers, 13(5), 1234–1245.
Lehmann, S., Bykov, V. J. N., Ali, D., Andrén, O., Cherif, H., Tidefelt, U., & Paul, C. (2022). Targeting p53 in vivo: A first-in-human study with p53 reactivating compound APR-246 in refractory hematologic malignancies and prostate cancer. Journal of Clinical Oncology, 40(15), 3009–3019.
Levine, A. J. (2019). Targeting therapies for the p53 protein in cancer treatments, Ann. Rev. Cancer Biol, 3, 21–34.
Levine, A. J. (2020). p53: 800 million years of evolution and 40 years of discovery. Nature Reviews Cancer, 20(8), 471–480.
Levine, A. J., & Oren, M. (2022). The first 30 years of p53: Growing ever more complex. Nature Reviews Cancer, 22(2), 112–124.
Li, V. D., Li, K. H., & Li, J. T. (2019). TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 Database. Journal of Cancer Research and Clinical Oncology, 145(3), 625–636. https://doi.org/10.1007/s00432-018-2817-z
Monti, P., Menichini, P., & Resnick, M. A. (2022). The dominant-negative effect of p53 mutants on p53-dependent gene expression. Frontiers in Oncology, 12.
Mueller, S., Grote, I., Bartels, S., Kandt, L., Christgen, H., Lehmann, U., Gluz, O., Graeser, M., Kates, R., Harbeck, N., Kreipe, H., & Christgen, M. (2023). p53 Expression in Luminal Breast Cancer Correlates With TP53 Mutation and Primary Endocrine Resistance. Modern Pathology, 36(4). https://doi.org/10.1016/j.modpat.2023.100100
Muller, P. A. J., & Vousden, K. H. (2021). Mutant p53 in cancer: New functions and therapeutic opportunities. Cancer Cell, 25(3), 304–317.
Nathan, C., Khandelwal, A. R., Wolf, G. T., Rodrigo, J. P., Mäkitie, A. A., Saba, N. F., Forastiere, A. A., Bradford, C. R., & Ferlito, A. (2022). TP53 mutations in head and neck cancer. Molecular Carcinogenesis, 61(4), 385–391. https://doi.org/10.1002/mc.23385
Olivier, M., Hollstein, M., & Hainaut, P. (2020). TP53 mutations in human cancers: Origins, consequences, and clinical use. . Cold Spring Harbor Perspectives in Medicine, 10(1), 1–17.
Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359(6382), 1350–1355. https://doi.org/10.1126/science.aar4060
Romanovsky, E., Kluck, K., Ourailidis, I., Menzel, M., Beck, S., Ball, M., Kazdal, D., Christopoulos, P., Schirmacher, P., Stiewe, T., Stenzinger, A., & Budczies, J. (2023). Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis. Cell Death Discovery, 9(1), 126. https://doi.org/10.1038/s41420-023-01413-1
Sallman, D. A. et al. (2021). Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. Journal of Clinical Oncology, 39(14), 1584–1594.
Saraswati, M., Harmastuti, N., & Herdwiani, W. (2020). Aktivitas Sitotoksik dan Ekspresi Protein p53 Bcl-2 Ekstrak dan Fraksi Daun Kersen (Muntingia calabura L.) terhadap Sel Kanker Payudara T47D. PHARMACY. Jurnal Farmasi Indonesia (Pharmaceutical Journal of Indonesia, 17(2), 292–303.
Singh, D. D., & Yadav, D. K. (2021). TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy. Biomedicines, 9(8), 876. https://doi.org/10.3390/biomedicines9080876
Sung, H. , F. J. , S. R. L. , L. M. , S. I. , J. A. , & B. 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.
Susanti, I. (2018). Analisis Bioinformatika Terhadap Gen TP53 (Tumor Protein 53) Tumor Suppressor pada Kanker Payudara. Majalah Kedokteran UKI, 165–176.
Suyanto, P. Y., Utomo, A. R., & Sandra, F. (2020). Mutasi Gen p53: Faktor Prediktif Kanker Payudara. . Indonesian Journal of Cancer, 2(4), 138–143.
Tsigkou, V., Oikonomou, E., Anastasiou, A., Lampsas, S., Zakynthinos, G. E., Kalogeras, K., Katsioupa, M., Kapsali, M., Kourampi, I., Pesiridis, T., Marinos, G., Vavuranakis, M.-A., Tousoulis, D., Vavuranakis, M., & Siasos, G. (2023). Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure. International Journal of Molecular Sciences, 24(5), 4321. https://doi.org/10.3390/ijms24054321
Voskarides, K., & Giannopoulou, N. (2023). The Role of TP53 in Adaptation and Evolution. Cells, 12(3), 1–11. https://doi.org/10.3390/cells12030512
Williams, D. S., Mouradov, D., Browne, C., Palmieri, M., Elliott, M. J., Nightingale, R., Fang, C. G., Li, R., Mariadason, J. M., Faragher, I., Jones, I. T., Churilov, L., Tebbutt, N. C., Gibbs, P., & Sieber, O. M. (2020). Overexpression of TP53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer. Modern Pathology, 33(3), 483–495. https://doi.org/10.1038/s41379-019-0353-2
Wiman, K. G., & Bykov, V. J. N. (2023). Mutant p53 and potential strategies for restoring tumor suppressor function. Annual Review of Pharmacology and Toxicology, 63, 421–440.
Yaeger, R., Chatila WK, & Lipsyc MD. (2018). Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell, 33, 125–136.
Yasser, M., Ribback, S., Evert, K., Utpatel, K., Annweiler, K., Evert, M., Dombrowski, F., & Calvisi, D. F. (2023a). Early Subcellular Hepatocellular Alterations in Mice Post Hydrodynamic Transfection: An Explorative Study. Cancers, 15(2), 328. https://doi.org/10.3390/cancers15020328
Zhang, S., Carlsen, L., Hernandez Borrero, L., Seyhan, A. A., Tian, X., & El-Deiry, W. S. (2022). Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules, 12(4), 1–26. https://doi.org/10.3390/biom12040548
Zhang, Y., Tang, Y., & Li, G. (2021). The role of p53-mediated apoptosis pathways in cancer therapy. Frontiers in Cell and Developmental Biology, 9.
2.png)
