埃及三阴性乳腺癌患者治疗反应和生存预测的分子生物标志物

Molecular biomarkers for prediction of response to treatment and survival in triple negative breast cancer patients from Egypt.

作者信息

Bahnassy Abeer, Mohanad Marwa, Ismail Manal F, Shaarawy Sabry, El-Bastawisy Ahmed, Zekri Abdel-Rahman N

机构信息

Molecular Pathology Unit, Pathology Department, National Cancer Institute, Cairo University, Egypt.

Department of Biochemistry, Faculty of Pharmacy, Misr University for Science and Technology, Egypt.

出版信息

Exp Mol Pathol. 2015 Oct;99(2):303-11. doi: 10.1016/j.yexmp.2015.07.014. Epub 2015 Jul 30.

DOI:10.1016/j.yexmp.2015.07.014

PMID:26232605

Abstract

BACKGROUND

Triple negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with reduced survival and poor prognosis. Increased VEGF-A, IGF-I, IGF-IR and TGF-β1 expressions were detected in breast cancer. However, little is known about their prognostic and predictive roles in TNBC.

AIM

We assessed the possible prognostic and predictive values of VEGF-A, IGF-I/IGF-IR and TGF-β1 in TNBC cases by measuring their protein and mRNA expression in TNBC and non-TNBC cases.

METHODS

VEGF-A, IGF-I, IGF-IR and TGF-β1 RNA and their corresponding proteins were assessed in 43 TNBCs, 53 non-TNBCs and 30 normal breast tissues (NBT) by real time PCR (qPCR) and immunohistochemistry (IHC); respectively. Results were related to clinico-pathological factors, response to treatment and survival rates.

RESULTS

Increased mRNA expression of VEGF-A, IGF-I, and IGF-IR was significantly higher in TNBC (65.1%, 65.1%, and 72.1%) than non-TNBC (28.1%, 33.96% and 28.3%) and NBT (0.00%) (P<0.001). Similarly, TNBC patients were significantly associated with high expression of VEGF-A, IGF-I, and IGF-IR proteins (67.44%, 62.79% and 83.72%) than non-TNBC (20.75%, 35.86% and 20.75%) and NBT (0.00%) (P<0.001). Protein and RNA expression levels of all studied markers showed high concordance in all investigated patients (correlation coefficient exceeding 0.5 and 0.4, respectively). In the TNBC group, metastasis and poor response to treatment were significantly associated with VEGF-A (P<0.001, P=0.007, respectively), IGF-I (P<0.001, P<0.001, respectively), IGF-IR (P=0.001, P=0.015, respectively) and TGF-β1 (P<0.001, P=0.007, respectively) protein levels. Multivariate logistic regression showed that IGF-I was the only independent prognostic factor for reduced OS (P=0.034) and DFS (P=0.026) in the TNBC patients.

CONCLUSIONS

VEGF-A, IGF-I and IGF-IR play an important role in the development and progression of TNBC compared to non-TNBC. Therefore, they could be used as prognostic and predictive biomarkers as well as candidates for targeted therapy. However, only IGF-I can predict survival in those patients.

摘要

背景

三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌表型，生存率降低且预后较差。在乳腺癌中检测到血管内皮生长因子A（VEGF-A）、胰岛素样生长因子I（IGF-I）、胰岛素样生长因子I受体（IGF-IR）和转化生长因子β1（TGF-β1）表达增加。然而，它们在TNBC中的预后和预测作用知之甚少。

目的

通过测量TNBC和非TNBC病例中VEGF-A、IGF-I/IGF-IR和TGF-β1的蛋白质和mRNA表达，评估其在TNBC病例中的可能预后和预测价值。

方法

分别通过实时定量聚合酶链反应（qPCR）和免疫组织化学（IHC），在43例TNBC、53例非TNBC和30例正常乳腺组织（NBT）中评估VEGF-A、IGF-I、IGF-IR和TGF-β1 RNA及其相应蛋白质。结果与临床病理因素、治疗反应和生存率相关。

结果

TNBC中VEGF-A、IGF-I和IGF-IR的mRNA表达增加（分别为65.1%、65.1%和72.1%），显著高于非TNBC（分别为28.1%、33.96%和28.3%）和NBT（0.00%）（P<0.001）。同样，TNBC患者中VEGF-A、IGF-I和IGF-IR蛋白的高表达（分别为67.44%、62.79%和83.72%）显著高于非TNBC（分别为20.75%、35.86%和20.75%）和NBT（0.00%）（P<0.001）。所有研究标志物的蛋白质和RNA表达水平在所有研究患者中显示出高度一致性（相关系数分别超过0.5和0.4）。在TNBC组中，转移和对治疗的不良反应与VEGF-A（分别为P<0.001、P=0.007）、IGF-I（分别为P<0.001、P<0.001）、IGF-IR（分别为P=0.001、P=0.015）和TGF-β1（分别为P<0.001、P=0.007）蛋白水平显著相关。多因素逻辑回归显示，IGF-I是TNBC患者总生存期（OS）降低（P=0.034）和无病生存期（DFS）降低（P=0.026）的唯一独立预后因素。