Vascular endothelial growth factor (VEGF) is an angiogenic factor and is an essential growth factor for vascular endothelial cells. VEGF is up regulated in many tumors and contributes to tumor angiogenesis; VEGF and VEGF receptors are expressed in numerous non-endothelial cells including tumor cells. sVEGFR2 and sVEGFR3, the soluble receptors of VEGF, regulate the formation of both lymphatic and blood vessels. Expression of VEGF and its receptors has been demonstrated in breast cancer cells and it enables the survival of tumor cells. Circulating VEGF also has been identified as a prognostic indicator for breast cancer. However, thus far, no prospective studies have examined the association between sVEGF receptors 2 and 3 and breast cancer incidence.
To examine this question, Dr. Holly Harris (Public Health Sciences Division) and colleagues, conducted a prospective case-control study nested within the Swedish Mammography Cohort (SMC) to investigate whether pre-diagnostic sVEGF receptor levels were associated with postmenopausal breast cancer risk. The results from their study were recently published in the International Journal of Molecular Epidemiology and Genetics.
SMC is a population-based prospective cohort study comprised of women from Västmanland and Uppsala counties, Sweden. The participants in the nested case-control study came from the SMC-Clinical, a subcohort, established between 2003 and 2009, of 5,022 women under the age of 85 and living in the city of Uppsala. Cases included participants who provided a blood sample and had a breast cancer diagnosis after blood collection and before December 31, 2011 (n=69). Controls were randomly selected from women without a breast cancer diagnosis who had provided a blood sample (n=719).
The investigators used logistic regression models to examine the association between sVEGFR receptor levels and breast cancer risk. They included the following adjustment factors in their model: age at visit, visit date, BMI at blood draw, height, education, oral contraceptive use, hormone replacement therapy use, age at menarche, age at menopause, parity/age at first birth, family history of breast cancer, benign breast disease, physical activity, and alcohol intake. In addition each biomarker is adjusted for the other biomarker. Using this model, they found sVEGFR2 levels were associated with breast cancer risk (odds ratio = 1.28; 95% confidence interval = 1.06-1.56 per 1000 ng/L increase in concentration) while sVEGFR3 levels were not related to such risk.
The VEGFR2 signaling pathway plays an important role in tumor angiogenesis, while VEGFR3 is involved in the development of lymph node metastasis. Thus the levels of sVEGFR3 could likely be associated with breast cancer progression and prognosis rather than initiation. This may explain why an association between sVEGFR3 levels and breast cancer risk were not found.
Dr. Harris further elaborates on the significance of these results, "while this is a small study it does provide some preliminary evidence that sVEGFR2 may be associated with breast cancer risk. This is the first study to examine this association prospectively with blood samples collected prior to breast cancer diagnosis and the next step for this line of research would be examining this association with a larger study population to confirm what we observed. With a larger sample we could also examine whether VEGFR2 is more strongly associated with certain tumor characteristics which could give us insight into how it is involved in breast cancer development in addition to its already established role in tumor angiogenesis. If confirmed, VEGFR2 could be evaluated as a potential early diagnostic marker of breast cancer."
Funding for this study was provided by Swedish Cancer Foundation, the Swedish Research Council, and the Conseil Regional d’Auvergne and the University d’Auvergne, Clermont-Ferrand, France.
Harris H,Wolk A,Larsson A,Vasson MP,Basu S. 2016. Soluble vascular endothelial growth factor receptors 2 (sVEGFR-2) and 3 (sVEGFR-3) and breast cancer risk in the Swedish Mammography Cohort. Int J Mol Epidemiol Genet. 7(1): 81-6. PMCID: PMC4858620.