Abstract
BackgroundThe overexpression of eukaryotic translation initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer. This study investigates the relationship between eIF4E and angiogenesis, as well as their prognostic impact in patients with human breast cancer.MethodsImmunohistochemical staining was used to determine protein expression of eIF4E, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and CD105 in a set of 122 formalin-fixed, paraffin-embedded primary breast cancer tissues. Expression of eIF4E in positive cells was characterized by cytoplasmic staining. Evaluation of VEGF and IL-8 in the same tissue established the angiogenic profiles, while CD105 was used as an indicator of microvessel density (MVD).ResultsA significant relationship was found between the level of eIF4E expression and histological grade (P = 0.016). VEGF, IL-8, and MVD were closely related to tumor grade (P = 0.003, P = 0.022, and P < 0.001, respectively) and clinical stage (P = 0.007, P = 0.048, and P < 0.001, respectively). Expression of eIF4E was also significantly correlated with VEGF (P = 0.007), IL-8 (P = 0.007), and MVD (P = 0.006). Patients overexpressing eIF4E had significantly worse overall (P = 0.01) and disease-free survival (P = 0.006). When eIF4E, histological grade, tumor stage, ER, PR, Her-2 status and the levels of VEGF, IL-8, MVD were included in a multivariate Cox regression analysis, eIF4E emerged as an independent prognostic factor for breast cancer (P = 0.001), along with stage (P = 0.005), node status (P = 0.046), and MVD (P = 0.004).ConclusionThese results suggest that higher eIF4E expression correlates with both angiogenesis and vascular invasion of cancer cells, and could therefore serve as a useful histological predictor for less favorable outcome in breast cancer patients, as well as represent a potential therapeutic target.
Highlights
The overexpression of eukaryotic translation initiation factor 4E, a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer
Immunochemical staining of eIF4E, vascular endothelial growth factor (VEGF), IL-8, and CD105 in breast cancer tissue In breast carcinoma, localization of eIF4E protein overexpression was mainly cytoplasmic in the cancer cells, but not in the adjacent normal-looking ductal epithelial cells and stromal elements
Consistent with the observation from the study in patients with stage I to III breast cancer by Byrnes et al [23], our results studied in all stages including stage IV breast cancer patients demonstrated that eIF4E overexpression is associated with high levels of VEGF and microvessel density (MVD) counts
Summary
The overexpression of eukaryotic translation initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer. Angiogenesis, which is essential for both tumor growth and metastasis, depends on the production of angiogenic factors by tumor cells and normal cells. At the beginning of this undesirable angiogenic process, two potent angiogenic growth factors, VEGF and IL-8, are known to stimulate endothelial cell proliferation, induce microvessel permeability, and begin to establish the tumor neovasculature [2]. VEGF, a well-known contributor to angiogenic processes in breast cancer, exhibits an increase in expression during pre-invasive cancer progression and is significantly associated with high intratumoral microvessel density [3,4,5,6]. The level of VEGF expression independently predicts diseasefree survival (DFS) and overall survival (OS) in invasive breast carcinoma [7,8]
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