Skip to main content Skip to main navigation menu Skip to site footer

Tumor Budding in Breast Carcinoma: Relation to E-Cadherin, MMP-9 Expression, and Metastasis Risk


Background: Tumor budding is a histopathologic entity refers to small cluster of cancer cells at the invasive edge of tumor. It was assumed that tumor budding is linked to epithelial-mesenchymal transition, an early event in metastasis. Objective: This study aimed to find out the correlation of tumor budding with E-cadherin and MMP-9 expression and risk of metastasis in breast carcinoma. Method: We investigated 35 cases breast carcinoma with metastasis and 35 cases without metastasis. The number of tumor budding was counted in cytokeratin-stained slides with 400x magnification (0.57 mm2). Result: Cut-off point by ROC analysis was 11 and the patient was categorized into low grade (0-10 buds) and high grade (11 or more buds) tumor budding. Inter-observer agreement was good with K value 0.914. Low level of E-cadherin was not significantly correlated with high grade tumor budding (p=0.660), meanwhile high level of MMP-9 was significantly correlated with high grade tumor budding (p=0.001). High grade tumor budding was a significant, independent risk factor of metastasis in breast carcinoma (OR=38.2, 95% CI 7.5-193.7, p<0.001). Conclusion: In conclusion, tumor budding grade is related to level of MMP-9 but has no correlation E-cadherin expression. High grade tumor budding is an independent risk factor of metastasis in breast carcinoma.


  1. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumor “budding†as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 2002;40:127-32.
  2. Prall F. Tumor budding in colorectal carcinoma. Histopathology2007;38:537-45.
  3. Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-Mesenchymal Transitions in Development and Disease. Cell2009;139:871-90.
  4. Lee K, Nelson CM. New Insight into Regulation of Epithelial-Mesenchymal Transition and Tissue Fibrosis. Int Rev Cell MolBiol2012;294:171-221.
  5. Demirkan, B. The roles of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in breast cancer bone metastases: potential targets for prevention and treatment. J. Cli. Med.2013;2:264-82.
  6. Allred C, Miller K, Viale G. Invasive breast carcinoma: Introduction and general features. Molecular testing for estrogen receptor, progesterone receptor, and HER2. In: Lakhani SR, Ellis IO, Schnitt SJ, Tang PH, van de Vijver MJ, eds. WHO classification of tumours of the breast, 4thed. IARC:Lyon, France. 2012. Pp:22-23.
  7. Golghirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Concensus on the Primary Therapy of Early Breast Cancer. Annal of Oncology 2012;22:1736-1747.
  8. Pai A, Baliga P, Shrestha BL. E-cadherin expression: a diagnostic utility for differentiating breast carcinomas with ductal and lobular morphologies. Journal of Clinical and Diagnostic Research 2013;7(5):840-844.
  9. Mahmood NA, Fahoury RM, Yaseen NY, Moustafa ME. Matrix metalloproteinases MMP2 and MMP9 expression in stages II-III breast cancer in Iraqi women. Journal of Medical and Biological Science Research 2015;1(3):30-37.
  10. Lugli A, Karamitopoulou E, Zlobec I. Tumor budding: a promising parameter in colorectal cancer. British Journal of Cancer 2012;106:1713-7.
  11. Canas-Marques R, Schnitt SJ. E-cadherin immunohistochemistry in breast pathology: uses and pitfalls. Histopathology2016;68:57-69.
  12. Liang F, Cao W, Wang Y, Li L, Zhang G, Wang Z. The prognostic value of tumor budding in invasive breast cancer. Pathol Res Pract 2013;209(5):269-75.
  13. Younis LK, Sakka HE, Haque I. The prognostic value of E-cadherin expression in breast cancer. International Journal of Health Science2007;1(1):43-51.
  14. Suciu C, Cimpean AM, Muresan AM, Izvernariu D, Raica M. E-cadherin expression in invasive breast cancer. Romanian Journal of Morphology and Embryology 2008;49(4):517-23.
  15. Brzozowska A, Sodolski T, Duma D, Mazurkiewicz T, Mazurkiewicz M. Evaluation of prognostic parameters of E-cadherin status in breast cancer treatment. Annals of Agricultural and Environment Medicine 2012;19(3):541-6.
  16. Qureshi HS, Linden M, Divine G, Raju UB. E-cadherin status in breast cancer correlates with histologic type but does not correlate with established prognostic parameters. Am J ClinPathol2006;125:377-85.
  17. Singhai R, Patil VW, Jaiswal SR, Patil SD, Tayade MB, Patil AV. E-cadherin as diagnostic biomarker in breast cancer. North American Journal of Medical Sciences 2011;3(5):227-33.
  18. Song J, Su H, Zhou Y, Guo L. Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: a meta analysis. Asian Pacific J Cancer Prev 2013;14(3):1615-1621.
  19. Yousef EM, Tahir RM, St-Pierre Y, Gaboury LA. MMP-9 expression varies according to molecular subtypers of breast cancer. BMC Cancer 2014;14(609):1-12.
  20. Wu X, Yang Q, Huang Y, She H, Liang J, Yang Q, Zhang Z. Expression and clinical significance of matrix metalloproteinase-9 in lymphatic invasiveness and metastasis of breast cancer. PLOS ONE 2014;9(5):1-6.
  21. Masuda R, Kijima H, Imamura N, Aruga N, Nakamura Y, Masuda D, Takeichi H, Kato N. Nakagawa T, Tanaka M, Inokuchi S, Iwazaki M. Tumor budding is a significant indicator of poor prognosis in lung squamous cell carcinoma patients. Mol Med Rep 2012;6(5):937-43.
  22. Kanazawa H, Mitomi H, Nishiyama Y, Kishimoto I, Fukui N, Nakamura T, Watanabe M. Tumor budding at invasive margins and outcome in colorectal cancer. Colorectal Dis2008;10:41-7.
  23. Salhia B, Trippel M, Gfatz K, Cihoric N, Grogg A, Ladrach C, Zlobec I, Tapia C. High tumor budding stratifies breast cancer with metastatic properties. Breast Cancer Res Treat2015;150:363-71.
  24. Gujam FJA, McMillan DC, Mohammed ZMA, Edwards J, Going JJ. The relationship between tumor budding, the tumor microenvirontment and survival in patients with invasive ductal breast cancer. British Journal of Cancer 2015;287:1-9.

How to Cite

Sriwidyani, N. P., Manuaba, I. B. T. W., Alit-Artha, I. G., & Mantik-Astawa, I. N. (2016). Tumor Budding in Breast Carcinoma: Relation to E-Cadherin, MMP-9 Expression, and Metastasis Risk. Bali Medical Journal, 5(3), 497–501.




Search Panel

Ni Putu Sriwidyani
Google Scholar
BMJ Journal

Ida Bagus Tjakra Wibawa Manuaba
Google Scholar
BMJ Journal

I Gusti Alit-Artha
Google Scholar
BMJ Journal

I Nyoman Mantik-Astawa
Google Scholar
BMJ Journal