Identification and verification of promising diagnostic genes in bisphenol A-associated breast cancer development via in silico analysis

Year 2023, Volume: 4 Issue: 2, 72 - 78, 30.08.2023

Mervenur Akkus Hamid Ceylan

https://doi.org/10.51753/flsrt.1223888

Cited By: 1

Abstract

Lifestyle patterns and exposure to toxic chemicals or environmental pollutants are the strongest risk factors for the chances of developing breast cancer, the leading and most lethal form of cancer in women. Bisphenol A (BPA), found in various consumer products, is known to deregulate multiple cellular signaling pathways, but its effect on cancer initiation and development in breast tissue has not yet been fully elucidated. Therefore, the identification of hub drivers is necessary to understand the molecular mechanisms underlying BPA-related malignancy and may help determine novel diagnosis and treatment strategies. This work aims at elucidating the molecular actors and mechanisms of action involved in BPA-induced breast cancer development using a bioinformatics analysis approach. A microarray dataset suitable for the study purposes was obtained from the publicly available Gene Expression Omnibus (GEO) repository, followed by DEG (differentially expressed genes) extraction, enrichment, and protein-protein interaction analyses to identify the hub genes. Expressional patterns, prognostic potentials, and immune infiltration levels of identified targets were tested and validated in silico using GEPIA2 and KM-plotter tools. According to PPI network results, CCNA2 and CCNB1 were identified as critical hub genes. Validation analyses clearly indicated that the identified genes are extremely critical in BPA-associated breast cancer processes. Findings from this study revealed that CCNA2 and CCNB1, two cell cycle signaling-related hub genes that are overexpressed as a consequence of BPA exposure, are strongly associated with breast cancer.

Keywords

Biomarker, BPA, breast cancer, cell cycle signaling, DEGs

References

• Almeida, S., Raposo, A., Almeida-Gonzalez, M., & Carrascosa, C. (2018). Bisphenol A: Food exposure and impact on human health. Comprehensive Reviews in Food Science and Food Safet, 17(6), 1503-1517.
• Barrett, T., Wilhite, S. E., Ledoux, P., Evangelista, C., Kim, I. F., Tomashevsky, M., ... & Soboleva, A. (2012). NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Research, 41(D1), D991-D995.
• Bondar, G., Kuo, J., Hamid, N., & Micevych, P. (2009). Estradiol-induced estrogen receptor-alpha trafficking. Journal of Neuroscience, 29(48), 15323-15330.
• Cai, Z., Wang, J., Li, Y., Shi, Q., Jin, L., Li, S., ... & Liu, Q. (2023). Overexpressed cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Science China Life Sciences, 66(1), 94-109.
• Castillo-Sanchez, R., Ramirez-Ricardo, J., Martinez-Baeza, E., Cortes-Reynosa, P., Candanedo-Gonzales, F., Gomez, R., & Salazar, E. P. (2020). Bisphenol A induces focal adhesions assembly and activation of FAK, Src and ERK2 via GPER in MDA-MB-231 breast cancer cells. Toxicology In Vitro, 66, 104871.
• Ceylan, H. (2021). Identification of hub genes associated with obesity-induced hepatocellular carcinoma risk based on integrated bioinformatics analysis. Medical Oncology, 38(6), 63.
• Ceylan, H. (2022). Integrated bioinformatics analysis to ıdentify alternative therapeutic targets for Alzheimer's disease: Insights from a synaptic machinery perspective. Journal of Molecular Neuroscience, 72(2), 273-286.
• Ceylan, H., Budak, H., Kocpinar, E. F., Baltaci, N. G., & Erdogan, O. (2019). Examining the link between dose-dependent dietary iron intake and Alzheimer's disease through oxidative stress in the rat cortex. Journal of Trace Elements in Medicine and Biology, 56, 198-206.
• Chandrashekar, D. S., Bashel, B., Balasubramanya, S. A. H., Creighton, C. J., Ponce-Rodriguez, I., Chakravarthi, B., & Varambally, S. (2017). UALCAN: A Portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 19(8), 649-658.
• CTD, (2023). Official Website of The Comparative Toxicogenomics Database, https://ctdbase.org/, Last accessed on August 10, 2023.
• DAVID, (2023). Official Website of The Database for Annotation, Visualization and Integrated Discovery, https://david.ncifcrf.gov/, Last accessed on August 10, 2023.
• Davis, A. P., Grondin, C. J., Johnson, R. J., Sciaky, D., Wiegers, J., Wiegers, T. C., & Mattingly, C. J. (2021). Comparative Toxicogenomics Database (CTD): update 2021. Nucleic Acids Research, 49(D1), D1138-D1143.
• Dehdashti, B., Nikaeen, M., Amin, M. M., & Mohammadi, F. (2023). Health risk assessment of exposure to Bisphenol A in polymeric baby bottles. Environmental Health Insights, 17, 11786302231151531.
• Ding, L., Cao, J., Lin, W., Chen, H., Xiong, X., Ao, H., Yu, M., Lin, J., & Cui, Q. (2020). The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. International Journal of Molecular Sciences, 21(6), 1-28.
• Dong, S., Huang, F., Zhang, H., & Chen, Q. (2019). Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma. Bioscience Reports, 39(2), BSR20182306. EPA. (2023). United States Environmental Protection Agency. https://www.epa.gov/. Last accessed on August 10, 2023.
• Fauconnier, M. B., Albert, C., Tondreau, A., Maumy, L., Rouzier, R., & Bonneau, C. (2023). Bisphenol A and breast cancer: State of knowledge and meta-analysis. Bulletin du Cancer, 110(2), 151-159.
• García-Gutiérrez, L., Bretones, G., Molina, E., Arechaga, I., Symonds, C., Acosta, J. C., ... & León, J. (2019). Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27. Scientific Reports, 9(1), 18693.
• GEO2R, (2023). Gene Expression Omnibus, https://www.ncbi.nlm.nih. gov/geo/geo2r/, Last accessed on August 10, 2023.
• GEPIA2, (2023). Gene Expression Profiling Interactive Analysis, http://gepia2.cancer-pku.cn/#index, Last accessed on August 10, 2023.
• Gyorffy, B. (2021). Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Computational and Structural Biotechnology Journal, 19, 4101-4109.
• Hong, X., Zhou, Y., Zhu, Z., Li, Y., Li, Z., Zhang, Y., ... & Shen, T. (2023). Environmental endocrine disruptor bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes. Environment International, 172, 107759.
• Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4(1), 44-57.
• Hwang, S., Lim, J. E., Choi, Y., & Jee, S. H. (2018). Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis. BMC Endocrine Disorders, 18(1), 81.
• JavanMoghadam, S., Weihua, Z., Hunt, K. K., & Keyomarsi, K. (2016). Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion. Cell Cycle, 15(12), 1579-1590.
• Jensen, L. J., Kuhn, M., Stark, M., Chaffron, S., Creevey, C., Muller, J., ... & von Mering, C. (2009). STRING 8-a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Research, 37(suppl_1), D412-D416.
• KM-plotter, (2023). Official Website of The Kaplan Meier plotter, https://kmplot.com/analysis/, Last accessed on August 10, 2023.
• Kustatscher, G., Grabowski, P., & Rappsilber, J. (2017). Pervasive coexpression of spatially proximal genes is buffered at the protein level. Molecular Systems Biology, 13(8), 937.
• Kwon, Y. (2022). Potential pro-tumorigenic effect of bisphenol A in breast cancer via altering the tumor microenvironment. Cancers, 14(12), 3021.
• Li, T., Fu, J., Zeng, Z., Cohen, D., Li, J., Chen, Q., Li, B., & Liu, X. S. (2020). TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Research, 48(W1), W509-W514.
• Li, L., Wang, M. Y., Jiang, H. B., Guo, C. R., Zhu, X. D., Yao, X. Q., Zeng, W. W., Zhao, Y., & Chi, L. K. (2023a). Bisphenol A induces testicular oxidative stress in mice leading to ferroptosis. Asian Journal of Andrology, 25(3), 375-381.
• Li, C., Sang, C., Zhang, S., Zhang, S., & Gao, H. (2023b). Effects of bisphenol A and bisphenol analogs on the nervous system. Chinese Medical Journal, 136(3), 295-304.
• Nardin, S., Mora, E., Varughese, F. M., D'Avanzo, F., Vachanaram, A. R., Rossi, V., Saggia, C., Rubinelli, S., & Gennari, A. (2020). Breast cancer survivorship, quality of life, and late toxicities. Frontiers in Oncology, 10, 864.
• Niu, Y., Xu, J., & Sun, T. (2019). Cyclin-dependent kinases 4/6 ınhibitors in breast cancer: Current status, resistance, and combination strategies. Journal of Cancer, 10(22), 5504-5517.
• Ogawa, M., Kitamoto, J., Takeda, T., & Terada, M. (2023). Bisphenol A prevents MCF-7 breast cell apoptosis via the inhibition of progesterone receptor transactivation. Journal of Biochemical and Molecular Toxicology, e23367.
• Pei, J., Wang, Y., & Li, Y. (2020). Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis. Journal of Translational Medicine, 18(1), 74.
• Pekarek, L., Torres-Carranza, D., Fraile-Martinez, O., García-Montero, C., Pekarek, T., Saez, M. A., ... & Ortega, M. A. (2023). An Overview of the Role of MicroRNAs on Carcinogenesis: A Focus on Cell Cycle, Angiogenesis and Metastasis. International Journal of Molecular Sciences, 24(8), 7268.
• Priyadarshini, E., Parambil, A. M., Rajamani, P., Ponnusamy, V. K., & Chen, Y. H. (2023). Exposure, toxicological mechanism of endocrine disrupting compounds and future direction of identification using nano-architectonics. Environmental Research, 225, 115577.
• Ritchie, S. C., Lambert, S. A., Arnold, M., Teo, S. M., Lim, S., Scepanovic, P., ... & Inouye, M. (2021). Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases. Nature Metabolism, 3(11), 1476-1483.
• Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Research, 13(11), 2498-2504.
• Stillwater, B. J., Bull, A. C., Romagnolo, D. F., Neumayer, L. A., Donovan, M. G., & Selmin, O. I. (2020). Bisphenols and risk of breast cancer: A narrative review of the ımpact of diet and bioactive food components. Frontiers in Nutrition, 7, 581388.
• STRING, (2023). Protein-Protein Interaction Networks Functional Enrichment Analysis, https://string-db.org/, Last accessed on August 10, 2023.
• Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of ıncidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249.
• Tang, Z., Kang, B., Li, C., Chen, T., & Zhang, Z. (2019). GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Research, 47(W1), W556-W560.
• TIMER2.0, (2023). Tumor IMmune Estimation Resource, http://cistrome.org/TIMER/, Last accessed on August 10, 2023.
• Tillett, T. (2009). Bisphenol A, chapter 2: new data shed light on exposure, potential bioaccumulation. Environmental Health Perspectives, 117(5), A210.
• UALCAN, (2023). The University of ALabama at Birmingham Cancer Data Analysis Portal, https://ualcan.path.uab.edu/, Last accessed on August 10, 2023.
• WHO, (2023). Official Website of World Health Organization, https://www.who.int/health-topics/cancer/, Last accessed on August 12, 2023.
• Xue, M., Zhang, K., Mu, K., Xu, J., Yang, H., Liu, Y., ... & Zhuang, T. (2019). Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56. Oncogenesis, 8(5), 30.
• Yadav, S. K., Bijalwan, V., Yadav, S., Sarkar, K., Das, S., & Singh, D. P. (2023). Susceptibility of male reproductive system to bisphenol A, an endocrine disruptor: Updates from epidemiological and experimental evidence. Journal of Biochemical and Molecular Toxicology, 37(4), e23292.
• Yesilkent, E. N., & Ceylan, H. (2022). Investigation of the multi-targeted protection potential of tannic acid against doxorubicin-induced kidney damage in rats. Chemico-Biological Interactions, 365, 110111.
• Zhang, X., Yang, L., Huang, B., Yin, J., & Wei, Y. (2023). Identification and validation of Cyclin A2 and Cyclin E2 as potential biomarkers in small cell lung cancer. Oncol Res Treat, 46(6), 246-258.
• Zhou, H., Lei, P. J., & Padera, T. P. (2021). Progression of metastasis through lymphatic system. Cells, 10(3), 627.
• Zuryn, A., Krajewski, A., Klimaszewska-Wisniewska, A., Grzanka, A., & Grzanka, D. (2019). Expression of cyclin B1, D1 and K in nonsmall cell lung cancer H1299 cells following treatment with sulforaphane. Oncology Reports, 41(2), 1313-1323.