Association of Matricellular Protein, Growth Factor, and Transcription Factor with Molecular Subtypes of Breast Cancer: A Case Control Study
Main Article Content
Keywords
Breast cancer, molecular subtypes, CCN6, VEGF-A, NF-κB, P65, CA 15-3
Abstract
Background: Breast cancer is a heterogeneous disease comprising molecular subtypes such as Luminal A, Luminal B, Human Epidermal Growth Factor 2 (HER-2)-Enriched, and Triple Negative, each with distinct clinical, molecular, and immunological features. Immunological markers play a critical role in modulating tumor behavior, angiogenesis, and immune evasion. Aim: This study aimed to identify key immunological markers that correlate with the molecular (intrinsic) subtypes of breast cancer and to explore their potential as prognostic factors. Methods: Serum samples from 180 breast cancer patients (56 untreated and 74 treated) were analyzed using Enzyme-Linked Immunosorbent Assay (ELISA) to determine the levels of four immunological biomarkers, including Cellular Communication Network Factor 6/WNT 1 Inducible Signaling Pathway Protein (CCN6/WISP3), Vascular Endothelial Growth Factor A (VEGF-A), Nuclear Factor Kappa B (NF-κB p65), and Cancer Antigen CA15-3. Demographic data and clinical parameters were collected using questionnaires. Results: Compared to the controls, patients with breast cancer exhibited significantly elevated levels of VEGF-A, NF-κB p65, and CA15-3, alongside decreased CCN6 levels (P < 0.05). At the molecular subtype level, HER2-enriched tumors showed the highest concentrations of CCN6 and VEGF-A, while elevated NF-κB p65 and CA15-3 levels were noted in Luminal B tumors, indicating the lowest CCN6 concentration in triple-negative tumors. Conclusions: This study demonstrates the roles of CCN6, VEGF, NF-κB p65, and CA15-3 as reliable biomarkers for distinguishing between molecular subtypes and suggests their potential as prognostic indicators.
References
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3. Aizaz M, Khan M, Khan FI, Munir A, Ahmad S, Obeagu EI. Burden of breast cancer: developing countries' perspective. Int J Innov Appl Res. 2023. doi:10.58538/IJIAR/2008.
4. Kaur R, Gupta S, Kulshrestha S, Khandelwal V, Pandey S, Kumar A, et al. Metabolomics-driven biomarker discovery for breast cancer prognosis and diagnosis. Cells. 2024;14(1):5. doi:10.3390/cells14010005. PMID:39791706; PMCID:PMC11720085.
5. Zhang X. Molecular classification of breast cancer: relevance and challenges. Arch Pathol Lab Med. 2023;147(1):46–51. doi:10.5858/arpa.2022-0070-RA.
6. 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. PMID:35674933; PMCID:PMC10030743.
7. Yasin AT, Ali ET, Mohammed AN, Shari FH. Comparative analyses of immune marker levels in seronegative and seropositive Iraqi rheumatoid arthritis patients. Iraqi Natl J Med. 2024;6(2):91–8. doi:10.37319/iqnjm.6.2.6.
8. Lorenzatti G, Huang W, Kleer CG. The emerging role of CCN6 in breast cancer invasion. Cellscience. 2009;6(2):146–57. PMID:29071006; PMCID:PMC5651983.
9. Huang W, Martin EE, Burman B, Gonzalez ME, Kleer CG, Huang W, et al. The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget. 2016;7(18):25180–93. doi:10.18632/oncotarget.7734. PMID:26933820; PMCID:PMC5041896.
10. 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. PMID:36983412; PMCID:PMC10056253.
11. Xue Y, Yang Y, Tian H, Quan H, Liu S, Zhang L, et al. Computational characterization of domain-segregated 3D chromatin structure and segmented DNA methylation status in carcinogenesis. Mol Oncol. 2022;16(3):699–716. doi:10.1002/1878-0261.13127. PMID:34708506; PMCID:PMC8807360.
12. Khongthong P, Roseweir AK, Edwards J. The NF-KB pathway and endocrine therapy resistance in breast cancer. Endocr Relat Cancer. 2019;26(6):R369–80. doi:10.1530/erc-19-0087. PMID:32013374.
13. Cheng X, Wang F, Qiao Y, Chen T, Fan L, Shen X, et al. Honokiol inhibits interleukin-induced angiogenesis in the NSCLC microenvironment through the NF-κB signaling pathway. Chem Biol Interact. 2023;370:110295. doi:10.1016/j.cbi.2022.110295. PMID:36470525.
14. Kremser M, Weiss N, Kaufmann-Stoeck A, Vierbaum L, Schmitz A, Schellenberg I, et al. Longitudinal evaluation of external quality assessment results for CA 15-3, CA 19-9, and CA 125. Front Mol Biosci. 2024;11:1401619. doi:10.3389/fmolb.2024.1401619. PMID:38966130; PMCID:PMC11222321.
15. Perrier A, Boelle PY, Chrétien Y, Gligorov J, Lotz JP, Brault D, et al. An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies. PLoS One. 2020;15(1):e0227356. doi:10.1371/journal.pone.0227356. PMID:31910438; PMCID:PMC6946590.
16. Ali ET, Mohammed AN, Khudairi AS, Sulaiman GM, Mohammed HA, Abomughayedh AM, et al. The extensive study of magnesium deficiency, 25-(OH) vitamin D3, inflammatory markers, and parathyroid hormone in relation to bone mineral density in Iraqi osteoporosis patients: a cross-sectional study. Health Sci Rep. 2025;8(4):e70641. doi:10.1002/hsr2.70641. PMID:40213265; PMCID:PMC11982515.
17. Mahmood M, Khurshid R, Mirza Iftikhar S, Ayyub A, Abbas Mughal A, Arif S. Correlation of heat shock protein 90 with nuclear factor kappa-B and vascular endothelial growth factor in breast cancer patients. MJCMH. 2025;7(1):103–8. doi:10.61982/medera.v7i1.222.
18. Pavitra E, Kancharla J, Gupta VK, Prasad K, Sung JY, Kim J, 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. PMID:37146418.
19. Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53. doi:10.1038/s41392-024-01757-9. PMID:38433280; PMCID:PMC10910037.
20. Mahaki H, Nobari S, Tanzadehpanah H, Babaeizad A, Kazemzadeh G, Mehrabzadeh M, et al. Targeting VEGF signaling for tumor microenvironment remodeling and metastasis inhibition: therapeutic strategies and insights. Biomed Pharmacother. 2025;186:118023. doi:10.1016/j.biopha.2025.118023. PMID:40164047.
21. Mohammed Muhibul G, Tariq Ali E, Ali Alrikabi M. Correlation between PD-L1 expression, demographic, and pathological characteristics in patients with breast cancer. Oncol Radiother. 2022;16(12):74–81.
22. Glassman I, Le N, Asif A, Goulding A, Alcantara CA, Vu A, et al. The role of obesity in breast cancer pathogenesis. Cells. 2023;12(16):2061. doi:10.3390/cells12162061. PMID:37626871; PMCID:PMC10453206.
23. Obeagu EI, Obeagu GU. Revolutionizing breast cancer monitoring: emerging hematocrit-based metrics – a narrative review. Ann Med Surg (Lond). 2025;87:3327–38. doi:10.1097/ms9.0000000000003020. PMID:40486605; PMCID:PMC12140720.
24. Divsalar B, Heydari P, Habibollah G, Tamaddon G. Hematological parameter changes in patients with breast cancer. Clin Lab. 2021;67(8). doi:10.7754/clin.lab.2020.201103. PMID:34383417.
25. Abbas AB, Al-Gamei S, Naser A, Al-Oqab A, Alduhami K, Al-Sabri M, et al. Comparison of hematological parameters and the associated factors among women with and without breast cancer: a case-control study. Breast Cancer (Dove Med Press). 2024;16:877–85. doi:10.2147/bctt.s497313. PMID:39678025; PMCID:PMC11645957.
26. Metwally IH, Zuhdy M, Hamdy O, Ezzat M, Elmoatasem M, Hassan A, et al. Evaluation of serum alkaline phosphatase as a marker of metastasis in early breast cancer. Rev Senol Patol Mamar. 2020;33(2):45–49. doi:10.1016/j.senol.2020.01.005.
27. Jiang T, Zeng Q, He J. Do alkaline phosphatases have great potential in the diagnosis, prognosis, and treatment of tumors? Transl Cancer Res. 2023;12(10):2932–45. doi:10.21037/tcr-23-1190. PMID:37969388; PMCID:PMC10643954.
28. Abdallah NM. Independence of liver, renal, and blood physiology in prognosis of pre-menopausal breast cancer. Bull Fac Zagazig Univ. 2022;3:91–5. doi:10.21608/bfszu.2022.144859.1150.
29. Sharma P, Chida K, Wu R, Tung K, Hakamada K, Ishikawa T, 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):120–30. doi:10.14740/wjon1993. PMID:39850522; PMCID:PMC11750749.
30. Smolanka II, Bagmut IY, Movchan OV, Sheremet MI, Bilyi OM, Lyashenko AO, et al. Features of VEGF and IL-6 expression in patients with inflammatory breast cancer considering molecular-biological characteristics. J Med Life. 2023;16(1):153–9. doi:10.25122/jml-2022-0172. PMID:36873124; PMCID:PMC9979174.
31. Zhi S, Chen C, Huang H, Zhang Z, Zeng F, Zhang S. Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment. Front Immunol. 2024;15:1370800. doi:10.3389/fimmu.2024.1370800. PMID:38799423; PMCID:PMC11116789.
32. Al-Mutairi MS, Habashy HO. Nuclear factor-κB clinical significance in breast cancer: an immunohistochemical study. Med Princ Pract. 2023;32(1):33–9. doi:10.1159/000527828. PMID:36412644; PMCID:PMC10267497.
33. Rasmy A, Abozeed W, Elsamany S, El Baiomy M, Nashwa A, Amrallah A, et al. Correlation of preoperative Ki67 and serum CA15.3 levels with outcome in early breast cancers: a multi-institutional study. Asian Pac J Cancer Prev. 2016;17(7):3595–600. PMID:27510014.
34. Ramchandwani DS, Dash DM, Panda DD, Sahoo DSS. Molecular and histopathological correlation of breast cancer subtypes with prognostic markers in Eastern India: a study from a tertiary care center. Eur J Cardiovasc Med. 2025;15:77–81.
35. Gonzalez ME, Fearon ER, Kleer C. Abstract PD5-06: CCN6 suppresses spindle metaplastic breast carcinoma in part via antagonizing Wnt/β-catenin signaling. Cancer Res. 2024;84(19):3235–49. doi:10.1158/0008-5472.can-23-4054. PMID:39024552.
36. Saputra TA, Indra I, Syamsu SA, Sampepajung E, Nelwan BJ, Hamid F, et al. Vascular endothelial growth factor-A expression is significantly correlated with HER2 expression in late-stage breast cancer patients. Breast Dis. 2022;41(1):433–8. doi:10.3233/bd-229006. PMID:36617773.
37. Farooq M, Bhat GhR, Besina S, Thakur N, Zahoor S, Rather RA, et al. Expression of HIF-1α and markers of angiogenesis and metabolic adaptation in molecular subtypes of breast cancer. Transl Med Commun. 2023;8(1):1–13. doi:10.1186/s41231-023-00135-x.
38. Barnes P, Mensah A, Derkyi-Kwarteng L, Adankwa E, Agbo E, Yahaya ES, 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):1–11. doi:10.1159/000539241. PMID:38723618; PMCID:PMC11324227.
39. Hercules SM, Alnajar M, Chen C, Mladjenovic SM, Shipeolu BA, Perkovic O, et al. Triple-negative breast cancer prevalence in Africa: a systematic review and meta-analysis. BMJ Open. 2022;12(5):e055735. doi:10.1136/bmjopen-2021-055735. PMID:35623750; PMCID:PMC9150263.
40. Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, et al. Risk factors and preventions of breast cancer. Int J Biol Sci. 2017;13(11):1387–97. doi:10.7150/ijbs.21635. PMID:29209143; PMCID:PMC5715522.
41. Muhabil GM, Ali ET, Alrikabi MA. Study the correlation between serum levels of PD-1/PD-L1, IFN-γ, and tumor marker CA 15-3 with demographic and clinical pathological characteristics of breast cancer patients [master's thesis]. Basrah, Iraq: University of Basrah; 2023.
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Jan 15, 2026
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Association of Matricellular Protein, Growth Factor, and Transcription Factor with Molecular Subtypes of Breast Cancer: A Case Control Study. Iraqi Natl J Med [Internet]. 2026 Jan. 15 [cited 2026 Jan. 17];8(1):112-2. Available from: https://www.iqnjm.com/index.php/homepage/article/view/308
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