Evaluation of serum CCN6, VEGF-A, and NF-κB p65 and their clinicopathological correlations in breast cancer
DOI:
https://doi.org/10.15584/ejcem.2026.3.12Keywords:
breast cancer, CA 15-3, CCN6, NF-κB p65, VEGF-AAbstract
Introduction and aim. CCN6, a transcriptional regulator within the CCN family, influences breast tumorigenesis by interacting with key angiogenic (VEGF-A) and inflammatory (NF-κB p65) pathways. This study establishes simultaneous evaluation of these serum biomarkers and comparison with CA 15-3 across untreated and treated breast cancer cohorts. This study aimed to evaluate their serum level and clinicopathological associations to understand their role in tumor progression and potential diagnostic utility.
Materials and methods. Serum biomarkers were measured via ELISA in 130 breast cancer patients (56 untreated and 74 treated) and 50 controls. Demographic and clinical data were collected through questionnaire-based interviews and clinicopathological data from medical records.
Results. CCN6 had the greatest effect size (F=1.10), followed by NF-κB p65 (F=0.51) and VEGF-A (F=0.22). The diagnostic efficacy (AUC=0.995; p=0.0001), sensitivity (96%), and specificity (100%) of CCN6 were superior to those of CA15-3 (AUC=0.855) and NF-κB p65 (AUC=0.813). Logistic regression demonstrated that downregulated CCN6 was inversely associated with disease outcome (OR=0.440; p=0.0001), whereas elevated NF-κB p65 (OR=1.737) levels increased breast cancer risk.
Conclusion. CCN6 showed promising diagnostic performance and exhibits an inverse association with breast cancer, outperforming NF-κB p65 and CA 15-3; these findings underscore CCN6's potential as a preliminary non-invasive diagnostic biomarker.
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References
Kleer CG. Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal. 2016;10(3):217-222. doi:10.1007/s12079-016-0345-7
Birkeness LB, Banerjee S, Quadir M, Banerjee SK. The role of CCNs in controlling cellular communication in the tumor microenvironment. J Cell Commun Signal. 2023;17(1):35-45. doi:10.1007/s12079-022-00682-2
Tran MN, Kleer CG. Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. J Cell Commun Signal. 2018;12(1):13-19. doi:10.1007/s12079-018-0451-9
Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
Gonzalez ME, Brophy B, Eido A, et al. CCN6 suppresses metaplastic breast carcinoma by antagonizing Wnt/β-Catenin signaling to inhibit EZH2-Driven EMT. Cancer Res. 2024;84(19):3235-3249. doi:10.1158/0008-5472.CAN-23-4054
Huang W, Martin EE, Burman B, et al. The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget. 2016;7(18):25180-25193. doi:10.18632/oncotarget. 7734
McMullen ER, Gonzalez ME, Skala SL, et al. CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast. Breast Cancer Res Treat. 2018;172(3):577-586. doi:10.1007/s10549-018-4960-2
Pavitra E, Kancharla J, Gupta VK, et al. The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy. Biomed Pharmacother. 2023;163:114822. doi:10.1016/j.biopha.2023.114822
Al Kawas H, Saaid I, Jank P, et al. How VEGF-A and its splice variants affect breast cancer development - clinical implications. Cell Oncol (Dordr). 2022;45(2):227-239. doi:10.1007/s13402-022-00665-w
Ghalehbandi S, Yuzugulen J, Pranjol MZI, Pourgholami MH. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. Eur J Pharmacol. 2023;949:175586. doi:10.1016/j.ejphar.2023.175586
Mao H, Zhao X, Sun SC. NF-κB in inflammation and cancer. Cell Mol Immunol. 2025;22(8):811-839. doi:10.1038/s41423-025-01310-w
Shaker SA, Alshufta SM, Gowayed MA, et al. Propolis-loaded nanostructured lipid carriers halt breast cancer progression through miRNA-223-related pathways: an in vitro/in vivo experiment. Sci Rep. 2023;13(1):15752. doi:10.1038/s41598-023-42709-7
Ryu JM, Kang D, Cho J, et al. Prognostic impact of elevation of cancer antigen 15-3 (CA15-3) in patients with early breast cancer with normal serum CA15-3 level. J Breast Cancer. 2023;26(2):126-135. doi:10.4048/jbc.2023.26.e17
Tang Z, Li L, Shen L, Shen X, Ju S, Cong H. Diagnostic value of serum concentration and integrity of circulating cell-free DNA in breast cancer: a comparative study with CEA and CA15-3. Lab Med. 2018;49(4):323-328. doi:10.1093/labmed/lmy019
Giuliano AE, Edge SB, Hortobagyi GN. Eighth edition of the AJCC cancer staging manual: breast cancer. Ann Surg Oncol. 2018;25(7):1783-1785. doi:10.1245/s10434-018-6486-6
Mohammed Muhibul G, Tariq Ali E, Ali Alrikabi M. Correlation between PD-L1 expression, demographic and pathological characters in patients with breast cancer. Oncol Radiother. 2022;16(12):74-81.
Huang W, Zhang Y, Varambally S, et al. Inhibition of CCN6 (Wnt-1-Induced Signaling Protein 3) Down-regulates E-Cadherin in the breast epithelium through induction of snail and ZEB1. Am J Pathol. 2008;172(4):893-904. doi:10.2353/ajpath.2008.070899
Ahmed KA, Hasib TA, Paul SK, et al. Potential role of CCN proteins in breast cancer: Therapeutic advances and perspectives. Curr Oncol. 2021;28(6):4972-4985. doi:10.3390/curroncol28060417
Behranvand N, Nasri F, Zolfaghari Emameh R, et al. Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunol Immunother. 2022;71(3):507-526. doi:10.1007/s00262-021-03013-3
Sharma P, Chida K, Wu R, et al. VEGFA gene expression in breast cancer is associated with worse prognosis, but better response to chemotherapy and immunotherapy. World J Oncol. 2025;16(1):120-130. doi:10.14740/wjon1993
Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. Int J Mol Sci. 2023;24(4):4002. doi:10.3390/ijms24044002
Brogowska KK, Zajkowska M, Mroczko B. Vascular endothelial growth factor ligands and receptors in breast cancer. J Clin Med. 2023;12(6):2412. doi:10.3390/jcm12062412
Zajkowska M, Lubowicka E, Malinowski P, Szmitkowski M, Ławicki S. Plasma levels of VEGF-A, VEGF B, and VEGFR-1 and applicability of these parameters as tumor markers in diagnosis of breast cancer. Acta Biochim Pol. 2018;65(4):621-628. doi:10.18388/abp.2018_2713
Al-Mutairi MS, Habashy HO. Nuclear Factor-κBcClinical significance in breast cancer: an immunohistochemical study. Med Princ Pract. 2023;32(1):33-39. doi:10.1159/000527828
Barnes P, Mensah A, Derkyi-Kwarteng L, et al. Prognostic significance of nuclear factor Kappa B (p65) among breast cancer patients in Cape Coast Teaching Hospital. Med Princ Pract. 2024;33(4):310-320. doi:10.1159/000539241
Sekacheva M, Boroda A, Fatyanova A, Rozhkov A, Bagmet N. Clinical validation of the novel CLIA-CA-62 assay efficacy for early-stage breast cancer detection. Front Oncol. 2023;13:1009863. doi:10.3389/fonc.2023.1009863
Henzler M, Willborn KC, Janni W, et al. Oncologic outcomes of young breast cancer patients according to tumor biology. Cancers (Basel). 2025;17(8):1333. doi:10.3390/cancers17081333
Intrieri T, Manneschi G, Caldarella A. 10-year survival in female breast cancer patients according to ER, PR and HER2 expression: a cancer registry population-based analysis. J Cancer Res Clin Oncol. 2022;149(8):4489-4496. doi:10.1007/s00432-022-04245-1
Chakraborty S, Banerjee S. Bridging molecular insights and clinical application: non-coding RNAs, targeted drug delivery, and metastatic breast cancer therapy. Discov Oncol. 2025;16(1):1413. doi:10.1007/s12672-025-03090-1
Muthanna FMS, Karuppannan M, Abdulrahman E, Uitrakul S, Rasool BAH, Mohammed AH. Prevalence and associated factors of anemia among breast cancer patients undergoing chemotherapy: a prospective study. Adv Pharmacol Pharm Sci. 2022;2022:7611733. doi:10.1155/2022/7611733
Yildirim S, Dogan A, Akdag G, et al. The role of laboratory indices on treatment response and survival in breast cancer receiving neoadjuvant chemotherapy. Sci Rep. 2024;14(1):1-9. doi:10.1038/s41598-024-63096-7
Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in breast cancer progression, diagnosis, and treatment. J Cancer. 2020;11(15):4474-4494. doi:10.7150/jca.44313
Al-Rubaye RHK, Kh Al-Jumaily RM. High tumor levels of Ki-67, VEGF, and endostatin are associated with progression of breast cancer in Iraqi women. Egypt J Hosp Med. 2023;90(1):79-83. doi:10.21608/ejhm.2023.279199
Li Y, Zhou L, San Z, Zhou P. Association of serum CA15-3, CA125, and TPS levels with clinicopathological factors in patients with breast cancer. J Biol Regul Homeost Agents. 2024;38(10):5957-5963. doi:10.23812/j.biol.regul.homeost.agents.20243810.475
Li Y, Zhao B, Peng J, et al. Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers. Drug Resist Updat. 2024;73:101042. doi:10.1016/j.drup.2023.101042
Kim JY, Jung E, Kim JM, et al. The role of follow-up CA15-3 in prognosis of breast cancer. Eur J Gynaecol Oncol. 2025;46(4):19-24. doi:10.22514/ejgo.2025.047
Abdul-Azees PA, Rajesh R, Block TJ, Dean DD, et al. CCN Proteins as matricellular regulators of bone in aging and disease. Curr Osteoporos Rep. 2025;23(1):23. doi:10.1007/s11914-025-00915-4
García-García VA, Alameda JP, Page A, Casanova ML. Role of NF-κB in ageing and age-related diseases: Lessons from genetically modified mouse models. Cells. 2021;10(8):1906. doi:10.3390/cells10081906
Cramer DW, Vitonis AF, Fichorova RN, Yamamoto HS, Mudugno F, Finn OJ. Variables affecting CA15.3 tumor antigen expression and antibodies against it in female National Health and Nutritional Survey (NHANES) participants. Cancer Epidemiol Biomarkers Prev. 2024;33(9):1211-1219. doi:10.1158/1055-9965.EPI-24-0187
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