Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E.
Angiogenesis is the formation of new blood vessels from the existing vasculature. Vascular endothelial growth factor (VEGF) is an endothelium-specific angiogenic factor strongly implicated in pathological angiogenesis. In this study, the mRNA and protein expression of the four alternatively spliced VEGF isoforms (121, 165, 189 and 206 amino acids) were examined in normal and malignant breast tissues. Three VEGF transcripts were detected in both (121>165>189), whereas only VEGF165 protein was detected. The tumours expressed more VEGF mRNA (P = 0.02) and protein (P < 0.0001), with eight-fold more VEGF protein generated per mRNA unit (P = 0.009). To examine this further, the expression of eIF-4E, a translation initiation factor, was examined. Increased eIF-4E mRNA levels were detected in the tumours (P < 0.0001) that correlated with VEGF mRNA (P = 0.0002), implying co-regulation of these genes. VEGF mRNA expression was elevated in tumours expressing the epidermal growth factor receptor (P < 0.01), but there was no difference according to oestrogen receptor status (P = 0.9), node status (P = 0.09) or between differing histologies (P = 0.4). These data suggest that elevated VEGF protein expression, by both enhanced transcription and translation, is a potential means by which tumour angiogenesis is induced in breast carcinomas. VEGF expression is also significantly associated with factors correlating with a poor outcome, implying a role in progression of this disease.
Scott
P A
PA
Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe, Oxford, UK.
Smith
K
K
Poulsom
R
R
De Benedetti
A
A
Bicknell
R
R
Harris
A L
AL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000378:metabolism; D066246:ErbB Receptors / Q000032:analysis; D039561:Eukaryotic Initiation Factor-4E; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007536:Isomerism; D008222:Lymphokines / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism* / Q000502:physiology; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D039561:Eukaryotic Initiation Factor-4E; D008222:Lymphokines; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors