p53 Correlation with Triple-negative Breast Cancer and Potential Treatments
DOI:
https://doi.org/10.62051/q0djfh23Keywords:
p53 mutant; triple-negative breast cancer; cellular signaling; immunotherapy.Abstract
Triple-negative breast cancer (TNBC) poses significant challenges in the field of oncology due to its prevalence and difficulty in treatment. TP53, which codes for a tumor-suppressing transcription factor p53, is crucial for the prevention of tumor development. When mutated, its role is reversed, as mutp53 provides new oncogenic properties and is correlated with the onset of cancers. Studies have presented a strong correlation between mutp53 and TNBC tumorigenesis by providing metastatic properties, uncontrolled proliferation, and immune evasion properties for the tumor cells. This review comprehensively examines the structural changes in mutp53, how the oncogenic properties are acquired through structural mutation, the cell signaling pathway that mutp53 alters that further leads to cancer development, and the novel treatments of TNBC using PRIMA-1, NVP-BEZ235, and histone deacetylase inhibitors (HDACIs). At last, the advantages of the treatments and challenges they currently are facing are critically evaluated. Further research directions, including examining toxicity and personalized treatments, are proposed for improving clinical outcomes for TNBC patients.
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[1] Almansour,N.M. (2022) Triple-Negative Breast Cancer: A brief review about epidemiology, risk factors, signaling pathways, treatment and role of artificial intelligence. Frontiers in Molecular Biosciences, 9, 836417. DOI: https://doi.org/10.3389/fmolb.2022.836417
[2] Alvarado-Ortiz, E., De La Cruz-López, K. G., Becerril-Rico, J., Sarabia-Sánchez, M. A., Ortiz-Sánchez, E. and García-Carrancá, A. (2021) Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches. Frontiers in Cell and Developmental Biology, 8, 607670. DOI: https://doi.org/10.3389/fcell.2020.607670
[3] Synnott, N., Murray, A., McGowan, P., Kiely, M., Kiely, P., O’Donovan, N., O’Connor, D., Gallagher, W., Crown, J. and Duffy, M. (2016) Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer? International Journal of Cancer, 140, 234–246. DOI: https://doi.org/10.1002/ijc.30425
[4] World Health Organization. (2024, March 13) Breast Cancer: Key Facts. Retrieved March 30, 2025, from https://www.who.int/news-room/fact-sheets/detail/breast-cancer.
[5] Yin, L., Duan, J., Bian, X. and Yu, S. (2020) Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Research, 22, 61. DOI: https://doi.org/10.1186/s13058-020-01296-5
[6] Kondapalli, K., Donepudi, M., Amos, S. and Venkanteshan, P. (2014) Breast cancer statistics and markers. Journal of Cancer Research and Therapeutics, 10, 506. DOI: https://doi.org/10.4103/0973-1482.137927
[7] Hill, D. A., Prossnitz, E. R., Royce, M. and Nibbe, A. (2020) Temporal trends in breast cancer survival by race and ethnicity: A population-based cohort study. PLoS ONE, 14, e0224064. DOI: https://doi.org/10.1371/journal.pone.0224064
[8] Wu, H., Do, C., Andrulis, I.L., John, E.M., Daly, M.B., Buys, S.S., Chung, W.K., Knight, J.A., Bradbury, A.R., Keegan, T.H.M., Schwartz, L., Krupska, I., Miller, R. L., Santella, R. M., Tycko, B. and Terry, M. B. (2020) Breast cancer family history and allele-specific DNA methylation in the legacy girls study. Epigenetics, 13, 240–250. DOI: https://doi.org/10.1080/15592294.2018.1435243
[9] Kolb, R. and Zhang, W. (2020). Obesity and breast cancer: a case of inflamed adipose tissue. Cancers, 12, 1686. DOI: https://doi.org/10.3390/cancers12061686
[10] Yaron, T., Cordova, Y. and Sprinzak, D. (2014). Juxtacrine signaling is inherently noisy. Biophysical Journal, 107, 2417–2424. DOI: https://doi.org/10.1016/j.bpj.2014.10.006
[11] Zhu, Y., Tian, Y., Du, J., Hu, Z., Yang, L., Liu, J. and Gu, L. (2012) DVL2-Dependent activation of DAAM1 and RHOA regulates WNT5A-Induced breast cancer cell migration. PLoS One, 7, e37823. DOI: https://doi.org/10.1371/journal.pone.0037823
[12] Jamdade, V.S., Sethi, N., Mundhe, N.A., Kumar, P., Lahkar, M. and Sinha, N. (2015) Therapeutic targets of triple‐negative breast cancer: a review. British Journal of Pharmacology, 172, 4228–4237. DOI: https://doi.org/10.1111/bph.13211
[13] Ali, R. and Wendt, M.K. (2020) The paradoxical functions of EGFR during breast cancer progression. Signal Transduction and Targeted Therapy, 2, 16042. DOI: https://doi.org/10.1038/sigtrans.2016.42
[14] Kastenhuber, E.R. and Lowe, S.W. (2020) Putting p53 in Context. Cell, 170, 1062–1078. DOI: https://doi.org/10.1016/j.cell.2017.08.028
[15] Williams, A.B. and Schumacher, B. (2020) p53 in the DNA-Damage-Repair Process. Cold Spring Harbor Perspectives in Medicine, 6(5), a026070. DOI: https://doi.org/10.1101/cshperspect.a026070
[16] Liu, T., Zhang, L., Joo, D. and Sun, S. (2020) NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2, 17023. DOI: https://doi.org/10.1038/sigtrans.2017.23
[17] U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, and HHS Vulnerability Disclosure. (2021, October) The TP53 Database. https://tp53.cancer.gov/.
[18] Olszewski, M., Pruszko, M., Snaar Jagalska, E., Zylicz, A. and Zylicz, M. (2019) Diverse and cancer type specific roles of the p53 R248Q gain of function mutation in cancer migration and invasiveness. International Journal of Oncology, 54, 1168-1182. DOI: https://doi.org/10.3892/ijo.2019.4723
[19] Lim, S., Kim, H. and Jung, G. (2010) p53 inhibits tumor cell invasion via the degradation of snail protein in hepatocellular carcinoma. FEBS Letters, 584, 2231–2236. DOI: https://doi.org/10.1016/j.febslet.2010.04.006
[20] He, C., Li, L., Guan, X., Xiong, L. and Miao, X. (2016) Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy. Chemotherapy, 62, 43–53. DOI: https://doi.org/10.1159/000446361
[21] Muller, P.A., Caswell, P.T., Doyle, B., Iwanicki, M.P., Tan, E.H., Karim, S., Lukashchuk, N., Gillespie, D.A., Ludwig, R.L., Gosselin, P., Cromer, A., Brugge, J.S., Sansom, O.J., Norman, J.C. and Vousden, K.H. (2009) Mutant p53 Drives Invasion by Promoting Integrin Recycling. Cell, 139, 1327–1341. DOI: https://doi.org/10.1016/j.cell.2009.11.026
[22] Cornel, A.M., Mimpen, I.L. and Nierkens, S. (2020) MHC Class I Downregulation in Cancer: Underlying mechanisms and potential targets for cancer immunotherapy. Cancers, 12, 1760. DOI: https://doi.org/10.3390/cancers12071760
[23] Cortez, M.A., Ivan, C., Valdecanas, D., Wang, X., Peltier, H. J., Ye, Y., Araujo, L., Carbone, D. P., Shilo, K., Giri, D. K., Kelnar, K., Martin, D., Komaki, R., Gomez, D.R., Krishnan, S., Calin, G.A., Bader, A.G. and Welsh, J.W. (2015) PDL1 Regulation by p53 via miR-34. JNCI Journal of the National Cancer Institute, 108, djv303. DOI: https://doi.org/10.1093/jnci/djv303
[24] Wang, Y., Yang, J., Zheng, H., Tomasek, G. J., Zhang, P., McKeever, P.E., Lee, E.Y. and Zhu, Y. (2009) Expression of Mutant p53 Proteins Implicates a Lineage Relationship between Neural Stem Cells and Malignant Astrocytic Glioma in a Murine Model. Cancer Cell, 15, 514–526. DOI: https://doi.org/10.1016/j.ccr.2009.04.001
[25] Cai, J., Xia, J., Zou, J., Wang, Q., Ma, Q., Sun, R., Liao, H., Xu, L., Wang, D. and Guo, X. (2020) The PI3K/mTOR dual inhibitor NVP‐BEZ235 stimulates mutant p53 degradation to exert anti‐tumor effects on triple‐negative breast cancer cells. FEBS Open Biology, 10, 535–545. DOI: https://doi.org/10.1002/2211-5463.12806
[26] Wang, Z., Chen, Z., Jiang, G., Wu, Y., Liu, T., Yi, Y., Zeng, J., Du, J. and Wang, H. (2016) Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells. Cellular Signalling, 28, 506–515. DOI: https://doi.org/10.1016/j.cellsig.2016.02.006
[27] Couch, F. J., Hart, S. N., Sharma, P., Toland, A. E., Wang, X., Miron, P., Olson, J. E., Godwin, A. K., Pankratz, V. S., Olswold, C., Nevanlinna, H., Yannoukakos, D., Slager, S. L., Vachon, C. M., Eccles, D. M. and Fasching, P. A. (2014) Inherited mutations in 17 breast cancer susceptibility genes among a large Triple-Negative breast cancer cohort unselected for family history of breast cancer. Journal of Clinical Oncology, 33, 304–311. DOI: https://doi.org/10.1200/JCO.2014.57.1414
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