Serum CD44 Variant 6 to CD44 Ratio and Vascular Endothelial Growth Factor Levels as Predictors of Metastasis in Luminal Subtype Breast Cancer
Abstract
BACKGROUND: Metastasis is the leading cause of mortality in luminal subtype breast cancer. While cluster of differentiation (CD)44 has been widely studied, the prognostic relevance of its isoforms particularly the CD44v6/CD44s ratio remains unclear. This study evaluates CD44v6, CD44s, vascular endothelial growth factor (VEGF), and the CD44v6/CD44s ratio as potential prognostic biomarkers for metastasis in luminal breast cancer.
METHODS: This case-control study included 38 luminal subtype breast cancer patients (18 with metastasis, 20 without metastasis). Serum levels of CD44v6, CD44s, VEGF, and the CD44v6/CD44s ratio were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Statistical analyses included ROC analysis to determine optimal cut-off points, logistic regression to assess risk factors, and correlation analysis for biomarker relationships.
RESULTS: A low CD44v6/CD44s ratio (<0.03) was identified as a significant independent factor for metastasis (adjusted OR 7.0, 95% CI: 1.2–40.6, p=0.03). While serum levels of CD44v6, CD44s, and VEGF were higher in the metastasis group, these individual markers showed a non-significant trend toward association with metastasis. A strong positive correlation was observed between CD44s and VEGF levels (r=0.7, p<0.01).
CONCLUSION: The CD44v6/CD44s ratio showed a significant association with metastasis and may have potential as a prognostic marker in luminal breast cancer. Further studies with larger sample sizes are needed to confirm these findings.
KEYWORDS: CD44v6, CD44s, VEGF, CD44v6/CD44s ratio, luminal breast cancer, metastasis
Full Text:
PDFReferences
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424, CrossRef.
Widiana IK, Irawan H. Clinical and subtypes of breast cancer in Indonesia. Asian Pacific J Cancer Care. 2020; 5(4): 281-5, CrossRef.
Dharmawan MS, Setiawan GB, Aryana IGNW. Karakteristik kanker payudara pada geriatri di rsup sanglah tahun 2015-2017. E-Jurnal Med Udayana. 2020; 9: 56-9, CrossRef.
Savitri M, Bintoro UY, Sedana MP, Diansyah MN, Romadhon PZ, Amrita PNA, et al. Circulating plasma miRNA-21 as a superior biomarker compared to CA 15-3: Assessment in healthy age matched subjects and different stage of breast cancer patients. Indones Biomed J. 2020; 12(2): 157-64, CrossRef.
Panigoro SS, Kurniawan A, Ramadhan, Sukartini N, Herqutanto, Paramita RI, et al. Amino acid profile of luminal A and B subtypes breast cancer. Indones Biomed J. 2023; 15(3): 269-76, CrossRef.
Abdihalim TS, Idris AAA. Mucin level as a potential biomarker for breast cancer diagnosis. Mol Cell Biomed Sci. 2022; 6(3): 117-20, CrossRef.
Engel P, Boumsell L, Balderas R, Bensussan A, Gattei V, Horejsi V, et al. CD Nomenclature 2015: Human leukocyte differentiation antigen workshops as a driving force in immunology. J Immunol. 2015; 195(10): 4555-63, CrossRef.
Prayogo AA, Wijaya AY, Hendrata WM, Looi SS, I'tishom R, Hakim L et al. Dedifferentiation of MCF-7 breast cancer continuous cell line, development of breast cancer stem cells (BCSCs) enriched culture and biomarker analysis. Indones Biomed J. 2020; 12(2): 115-23, CrossRef.
Porcellini S, Asperti C, Corna S, Cicoria E, Valtolina V, Stornaiuolo A, et al. CAR T cells redirected to CD44v6 control tumor growth in lung and ovary adenocarcinoma bearing mice. Front Immunol. 2020; 11: 99, CrossRef.
Qiao GL, Song LN, Deng ZF, Chen Y, Ma LJ. Prognostic value of CD44v6 expression in breast cancer: A meta-analysis. Onco Targets Ther. 2018; 11: 5451-7, CrossRef.
Perrot-Applanat M, Di Benedetto M. Autocrine functions of VEGF in breast tumor cells: Adhesion, survival, migration and invasion. Cell Adh Migr. 2012; 6(6): 547-53, CrossRef.
Guntarno NC, Rahaju AS, Kurniasari N. The role of MMP-9 and VEGF in the invasion state of bladder urothelial carcinoma. Indones Biomed J. 2021; 13(1): 61-7, CrossRef.
Widowati W, Jasaputra DK, Sumitro SB, Widodo MA, Afifah E, Rizal R, et al. Direct and indirect effect of TNFα and IFNγ toward apoptosis in breast cancer cells. Mol Cell Biomed Sci. 2018; 2(2): 60-9, CrossRef.
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more 'personalized' approach to cancer staging. CA Cancer J Clin. 2017; 67(2): 93-9, CrossRef.
Ristamäki R, Joensuu H, Jalkanen S. Serum CD44 in non-Hodgkin's lymphoma. Leuk Lymphoma. 1999; 33(5-6): 433-40, CrossRef.
Baek JM, Jin Q, Ensor J, Boulbes DR, Esteva FJ. Serum CD44 levels and overall survival in patients with HER2-positive breast cancer. Breast Cancer Res Treat. 2011; 130(3): 1029-36, CrossRef.
Lackner C, Moser R, Bauernhofer T, Wilders-Truschnig M, Samonigg H, Berghold A, et al. Soluble CD44 v5 and v6 in serum of patients with breast cancer. Correlation with expression of CD44 v5 and v6 variants in primary tumors and location of distant metastasis. Breast Cancer Res Treat. 1998; 47(1): 29-40, CrossRef.
Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest. 2011; 121(3): 1064-74, CrossRef.
Salven P, Mänpää H, Orpana A, Alitalo K, Joensuu H. Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin cancer Res an Off J Am Assoc Cancer Res. 1997; 3(5): 647-51, PMID.
Salven P, Perhoniemi V, Tykkä H, Mäenpää H, Joensuu H. Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res Treat. 1999; 53(2): 161-166, CrossRef.
Coskun U, Günel N, Toruner FB, Sancak B, Onuk E, Bayram O, et al. Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer. Neoplasma. 2003; 50(1): 41-6, PMID.
Iovino F, Ferraraccio F, Orditura M, Antoniol G, Morgillo F, Cascone T, et al. Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer. Cancer Invest. 2008; 26(3): 250-5, CrossRef.
Banys-Paluchowski M, Witzel I, Riethdorf S, Pantel K, Rack B, Janni W, et al. The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer. Breast Cancer Res Treat. 2018; 172(1): 93-104, CrossRef.
Ryu D, Ryoo IG, Kwak MK. Overexpression of CD44 standard isoform upregulates HIF-1α signaling in hypoxic breast cancer cells. Biomol Ther. 2018; 26(5): 487-93, CrossRef.
Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018; 11: 46, CrossRef.
Karar J, Maity A. PI3K/AKT/mTOR Pathway in Angiogenesis. Front Mol Neurosci 2011; 4: 51, CrossRef.
DOI: https://doi.org/10.18585/inabj.v17i3.3586
Copyright (c) 2025 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute
