Abstract
PurposePro-angiogenic factors are positively associated with breast tumor staging and poorer prognosis, but their role in the etiology of breast cancer has not been assessed.MethodsWe measured serum levels of the pro-angiogenic vascular endothelial growth factor A (VEGF), and placental growth factor (PlGF) and anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) in 352 incident breast cancer cases [mean age at diagnosis 67 (range 55–83)] and 352 non-cases in the prostate, lung, colorectal, and ovarian screening trial (women enrolled 1993–2001, followed through 2005) matched on age and date of enrollment. Cases were followed on average 4.2 years from blood draw to diagnosis, range 3.9–12.8 years; 53 % were estrogen receptor positive/progesterone receptor positive (ER+/PR+), and 13 % were ER−/PR−. Quartile-specific hazard ratios (HR) and 95 % confidence intervals (CI) were estimated using weighted Cox proportional hazards regression models adjusted for known breast cancer risk factors. An ordinal variable for the angiogenic markers was used to test for trend in the HR.ResultsComparing the highest to lowest quartile, multivariable HR were 0.90 for VEGF (95 % CI 0.33–2.43, p trend = 0.88), 1.38 for sFlt-1 (95 % CI 0.63–3.04, p trend = 0.63), and 0.62 for PlGF (95 % CI 0.19–2.00, p trend = 0.73). Risk patterns were not altered when all angiogenic markers were included in the model simultaneously, or by restricting analyses to invasive breast cancers, to cases diagnosed two or more years after blood collection or to ER+ tumors.ConclusionsThere was no evidence of an increased breast cancer risk associated with circulating levels of pro-angiogenic markers VEGF and PlGF or a reduced risk with circulating levels of anti-angiogenic marker sFlt-1.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-016-0779-5) contains supplementary material, which is available to authorized users.
Highlights
Numerous studies show poorer survival in women with breast cancer tumors that overexpress angiogenesis-promoting proteins including vascular endothelial growth factor A (VEGF) [1,2,3,4] and placental growth factor (PlGF) [5, 6], but the prognostic utility of these markers in newly diagnosed cancer is not clear [1, 7, 8], and their potential etiologic roles in breast cancer have not been well studied
There was no evidence of an increased breast cancer risk associated with circulating levels of pro-angiogenic markers VEGF and PlGF or a reduced risk with circulating levels of anti-angiogenic marker soluble fms-like tyrosine kinase-1 (sFlt-1)
It entails a complex coordination between pro- and anti-angiogenic factors, and increasing evidence suggests that sex steroids may regulate their production in a tissue-specific manner
Summary
Numerous studies show poorer survival in women with breast cancer tumors that overexpress angiogenesis-promoting proteins including VEGF ( known as VEGF-A) [1,2,3,4] and PlGF (a member of the VEGF family) [5, 6], but the prognostic utility of these markers in newly diagnosed cancer is not clear [1, 7, 8], and their potential etiologic roles in breast cancer have not been well studied. While angiogenesis is a quiescent process in most adult tissues, it is critical to normal physiologic processes such as inflammation, wound healing, embryogenesis, and the menstrual cycle, as well as to the pathologic processes of tumor growth and metastasis. It entails a complex coordination between pro- and anti-angiogenic factors, and increasing evidence suggests that sex steroids may regulate their production in a tissue-specific manner. Women with a history of preeclampsia, who during their pregnancy experience pronounced elevations in the antiangiogenic factor sFlt-1 ( known as soluble VEGF receptor 1) along with low circulating VEGF and PlGF, have a reduced risk of subsequent breast cancer [13,14,15,16]. Pre-diagnostic serum samples from the screening arm of the prostate, lung, colon, and ovary cancer trial (PLCO) [18], we assessed whether healthy women with high levels of VEGF and PlGF along with low circulating sFlt-1 would be at elevated risk of breast cancer
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