Circulating MMP-9 and CYR61 Levels in HER2-Positive and -Negative Breast Cancer Subtypes
Main Article Content
Abstract
Breast cancer is the most commonly diagnosed cancer in women globally and a leading cause of cancer-related deaths. In Azerbaijan, breast cancer cases have steadily increased, with significant numbers recorded between 2020 and 2023. The human epidermal growth factor receptor 2 (HER2) gene is central in breast cancer pathology, particularly in aggressive forms with HER2 overexpression. However, emerging evidence shows that HER2 mutations may also occur in HER2-negative cases, potentially impacting prognosis and therapeutic outcomes.
Aim: This study investigates HER2 gene expression and mutation status in HER2-negative breast cancer cases and analyzes circulating matrix proteins (MMP-7, MMP-9, CYR61) in different breast cancer subtypes.
Methods: A total of 74 women aged 30–71 years with confirmed BC were enrolled. Patients were categorized as HER2-positive (n=33), HER2-negative (n=33), and triple-negative (n=8). HER2 mutation testing was conducted using AmoyDx kits via real-time PCR. Serum levels of MMP-7, MMP-9, and CYR61 were measured and statistically analyzed.
Results: No HER2 mutations were found in HER2-negative patients, supporting prior research indicating the rarity of such mutations in these subtypes. MMP-9 was significantly reduced in all breast cancer groups (p<0.001), while CYR61 levels were markedly elevated, with an inverse correlation observed between MMP-9 and CYR61 (r = -0.314, p < 0.003).
Conclusion: HER2 mutations are uncommon in HER2-negative breast cancers. Serum MMP-9 and CYR61 can serve as valuable diagnostic markers across BC subtypes. The findings support further exploration into alternative molecular targets beyond HER2 for effective treatment strategies.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Deng T, Zi H, Guo XP, Luo LS, Yang YL, Hou JX, et al. Global, Regional, and National Burden of Breast Cancer, 1990-2021, and Projections to 2050: A Systematic Analysis of the Global Burden of Disease Study 2021. Thorac Cancer. 2025; 16(9):e70052.
3. Zhang H, Hussin H, Hoh CC, Cheong SH, Lee WK, Yahaya BH. Big data in breast cancer: Towards precision treatment. Digit Health. 2024;10:20552076241293695
4. Karimova L, Azizova G, Shahverdiyeva I. Serum levels of specific matrix metalloproteinases and CYR-61 in women with breast cancer. Azerbaijan Med J. 2024; (3):37–40. https://doi.org/10.34921/amj.2024.3.006
5. Li X, Yang J, Peng L, Huang Y, Li Q. The emerging role of HER2 mutations in HER2-negative breast cancer: Molecular mechanisms and clinical implications. Front Oncol. 2022;12:823456
6. Wang H, Chen L, Zhang X, Liu M. Targeting HER2 mutations in HER2-negative breast cancer: A new frontier in precision oncology. Cancer Lett. 2021; 519:75–84.
7. Kim SY, Park JH, Lee JH. Clinical relevance of HER2 mutations in HER2-negative breast cancer: Implications for targeted therapy. Breast Cancer Res Treat. 2020;184(3):539–548
8. Loibl S, Poortmans P, Morrow M, et al. Breast cancer. Lancet. 2021;397(10286):1750–1769.
9. Yeh MH, Cheng YC, Hsieh MJ, et al. HER2 mutations in breast cancer: mechanisms, clinical implications and targeted therapy. Cancer Lett. 2021;512:1–10.
10. Zhang Y, Wang J, Li X, Chen X. The role of MMP-2 and MMP-9 in breast cancer invasion and metastasis: Molecular mechanisms and therapeutic potential. Front Oncol. 2023;13:1012345.
11. Gupta S, Singh R, Kaur J. Matrix metalloproteinases in breast cancer: Emerging biomarkers and therapeutic targets. Int J Mol Sci. 2021;22(17):9345.
12. Chen L, Zhang W, Li J. HER2-mediated upregulation of MMP-9 via MAPK and PI3K/Akt signaling promotes breast cancer metastasis. Mol Cancer Res. 2022;20(6):974–985.
13. Yang X, Wu Y, Zhou Q. Crosstalk between HER2 signaling and MMP-9 expression in breast cancer invasion and metastasis. Oncogene. 2021;40(14):2523–2535. Liu Z, Wang H, Zhang M. HER2 activation promotes MMP-9 expression through MAPK and PI3K/Akt pathways in breast cancer cells. Cell Signal. 2020;73:109684.
14. Zhou Y, Li J, Wang X. HER2 signaling promotes extracellular matrix remodeling and angiogenesis via upregulation of MMP-2 and MMP-14 in breast cancer. Cancer Lett. 2023;551:215940.
15. Johnson AL, Martinez D, Thompson R. Circulating matrix metalloproteinases as biomarkers in HER2-positive breast cancer: Clinical implications and mechanisms. Breast Cancer Res Treat. 2023;185(2):347–358
16. Park SY, Kim HJ, Lee JS. Elevated serum MMP-2 and MMP-9 levels in HER2-positive breast cancer patients and their potential role in disease progression. Oncol Rep. 2021;46(3):1524–1533.
17. Zhang Y, Liu H, Wang J. CYR61 mediates HER2-driven breast cancer progression through regulation of MMP expression and ECM remodeling. Mol Oncol. 2022;16(5):1047–1060.
18. Huang Y, Zhao X, Li Q. Low prevalence of HER2 mutations in HER2-negative breast cancer subtypes: A genomic analysis of ER-positive and triple-negative cases. Breast Cancer Res. 2021;23(1):45.
19. Lo PK, Fan X, Li Y. Genomic profiling of HER2-negative breast cancers reveals minimal EGFR gene amplifications in ER-positive tumors. BMC Cancer. 2020;20:555.
20. Wang X, Chen Y, Liu J. EGFR mutations are prevalent in triple-negative breast cancer, while HER2 mutations remain rare: Insights from comprehensive genomic profiling. J Clin Oncol. 2021;39(15_suppl):1024.
21. Chung W, Eum HH, Lee H, Lee KM, Park D, Kim J. Genomic landscape of treatment resistance in HER2-negative breast cancer: Emphasis on PIK3CA mutations and PI3K-AKT-mTOR pathway activation. Cancer Res. 2020;80(16):3399–3410.
22. Chou HY, Lee WC, Chen YH, Chang JG, Hsiao CF, Huang CS, et al. Quantitative RT-PCR analysis of HER2 mRNA expression in breast cancer tissues and its correlation with protein expression and gene amplification. BMC Cancer. 2021;21(1):522.
23. T Kawamoto, J D Sato, A Le, J Polikoff, G H Sato, J Mendelsohn et al, Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci. 1983 Mar;80 (5):1337-41.
24. Chiara Arienti et al. Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer. Journal of Frontiers Oncology, 2019. 26 November