Vascular endothelial growth factor (VEGF) -A, -C and VE-cadherin as potential biomarkers in early breast cancer patients

Jelena Milovanović; Tijana Vujasinović; Nataša Todorović-Raković; John Greenman; Jelena Hranisavljević; Marko Radulovic

doi:10.1016/j.prp.2023.154923

Vascular endothelial growth factor (VEGF) -A, -C and VE-cadherin as potential biomarkers in early breast cancer patients

Pathol Res Pract. 2023 Dec:252:154923. doi: 10.1016/j.prp.2023.154923. Epub 2023 Nov 5.

Authors

Jelena Milovanović¹, Tijana Vujasinović², Nataša Todorović-Raković², John Greenman³, Jelena Hranisavljević⁴, Marko Radulovic²

Affiliations

¹ Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia. Electronic address: jelena.mil10@gmail.com.
² Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
³ Centre for Biomedicine, University of Hull, Hull, UK.
⁴ Department for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinča - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

PMID: 37948997
DOI: 10.1016/j.prp.2023.154923

Abstract

Background: Vascular endothelial growth factor (VEGF) -A and -C act as multifunctional molecules and growth factors, while VE-cadherin (cadherin 5, CDH5) is the endothelial junction protein.

Aim: To assess the relationship between intratumoral VEGF -A, -C and CDH5 levels and clinical outcome, in primary, early-stage, breast cancer patients.

Patients and methods: The study included 69 node-negative (N0) breast cancer patients, all of whom had not received any prior hormonal or chemotherapeutic systemic therapy that would affect the course of disease. The median follow-up period was 144 months. Intratumoral mRNA levels of VEGF -A, -C and CDH5 were determined by RT-qPCR. Prognostic performance was evaluated by Cox proportional hazards regression, Kaplan-Meier analysis, as well as by the multivariable approach based on the least absolute shrinkage and selection operator (LASSO) logit regression. Classification of patients into the low and high subgroups was performed using the outcome-oriented cut-off point categorization approach.

Results: Of the measured mRNAs, only CDH5 mRNA (t = -2.17; p = 0.04) and VEGF-C mRNA (t = -2.41; p = 0.03) showed significant differences between values in patient subgroups with distant metastasis and those without recurrences, respectively. These t-test results were in agreement with the Cox regression by which CDH5 mRNA reached the most pronounced hazard ratio (HR=2.07; p = 0.05), followed by VEGF-C mRNA (HR=1.59; p = 0.005). HR values above 1.0 indicate that high levels of either CDH5 or VEGF-C mRNAs associated with a higher risk of poor clinical outcome. Distant recurrence incidence was 26% for the CDH5^high and 3% for the CDH5^low subgroup (Kaplan-Meier analysis). Distant recurrence incidence was 23% for the VEGF-C^high and 0% for VEGF-C^low subgroup. The independent prognostic value of VEGF-C mRNA was confirmed by LASSO regression.

Conclusion: Intratumoral VEGF-A levels did not associate with disease outcome in primary, early-stage, breast cancer patients, whilst raised levels of either CDH5 or VEGF-C prognosticated a high risk of distant metastasis.

Keywords: Biomarker; Breast cancer; CDH5; Prognosis; VE-cadherin; VEGF.

MeSH terms

Antigens, CD / metabolism
Biomarkers, Tumor / analysis
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Female
Humans
Prognosis
RNA, Messenger / genetics
Vascular Endothelial Growth Factor A* / genetics
Vascular Endothelial Growth Factor A* / metabolism
Vascular Endothelial Growth Factor C / genetics
Vascular Endothelial Growth Factor C / metabolism
Vascular Endothelial Growth Factors

Substances

Vascular Endothelial Growth Factor A
cadherin 5
Vascular Endothelial Growth Factor C
Antigens, CD
Vascular Endothelial Growth Factors
RNA, Messenger
Biomarkers, Tumor