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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2016, Vol. 10 ›› Issue (02) : 76 -81. doi: 10.3877/cma.j.issn.1674-0807.2016.02.003

论著

血管生成素样蛋白3、4 在浸润性乳腺癌中的表达及临床意义
毛枫枫1, 章佳新1,†()   
  1. 1.225001 扬州大学临床医学院苏北人民医院甲乳外科
  • 收稿日期:2015-10-31 出版日期:2016-04-01
  • 通信作者: 章佳新

Expressions of Angptl 3 and Angptl 4 in invasive breast cancer and clinical significance

Fengfeng Mao1, Jiaxin Zhang1,†()   

  1. 1.Department of Thyroid and Breast Surgery,Subei People's Hospital,Collge of Clinical Medicine,Yangzhou University, Yangzhou 225001,China
  • Received:2015-10-31 Published:2016-04-01
  • Corresponding author: Jiaxin Zhang
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毛枫枫, 章佳新. 血管生成素样蛋白3、4 在浸润性乳腺癌中的表达及临床意义[J/OL]. 中华乳腺病杂志(电子版), 2016, 10(02): 76-81.

Fengfeng Mao, Jiaxin Zhang. Expressions of Angptl 3 and Angptl 4 in invasive breast cancer and clinical significance[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2016, 10(02): 76-81.

目的

检测血管生成素样蛋白(angiopoietin-like protein, Angptl) 3 和Angptl 4 在浸润性乳腺癌组织中的表达及其临床意义,为乳腺癌的治疗及预后提供有价值的生物学指标。

方法

用随机数字表法收集苏北人民医院2007—2009年手术切除浸润性乳腺癌标本70 例,乳腺纤维腺瘤标本30 例,采用免疫组织化学SP 法,检测肿瘤标本中Angptl 3 和Angptl 4 的表达。 采用χ2 检验分析两种蛋白在乳腺癌和乳腺纤维腺瘤中是否具有表达差异性,χ2 检验和Fisher 确切概率法分析两种蛋白与乳腺癌临床病理特征之间的关系,Spearman 相关分析法分析Angptl 3 和Angptl 4 两种蛋白在浸润性乳腺癌中表达的相关性,并采用Kaplan-Meier 法及Cox 比例风险模型进行浸润性乳腺癌患者的生存分析。

结果

Angptl 3 在浸润性乳腺癌和乳腺纤维腺瘤中的阳性表达率分别为75.7%(53/70)和46.7%(14/30)(χ2=8.014,P=0.005),Angptl 4 在浸润性乳腺癌和乳腺纤维腺瘤中的阳性表达率分别是68.6%(48/70)和36.7%(11/30)(χ2=8.837,P=0.003),差异均有统计学意义。 Angptl 3 的表达在不同肿瘤直径、腋窝淋巴结转移、TNM 分期、ER 表达的患者中差异有统计学意义(χ2 =6.000、5.598、9.714、8.753,P＜0.050)。 在70 例浸润性乳腺癌中,Angptl 4 的表达在不同肿瘤直径、腋窝淋巴结转移、TNM 分期的患者中差异有统计学意义(χ2=8.762、6.526、5.701, P＜0.050)。 Angptl 3 和Angptl 4 表达呈正相关(P=0.005, r=0.334)。 Kaplan-Meier 分析结果表明,Angptl 3 和Angptl 4 阴性表达的患者总生存期均优于阳性表达的患者(χ2=9.376、7.628,P=0.002、0.006)。 Cox 多因素生存分析结果表明,年龄、组织学分级、肿瘤直径、ER、PR 是影响预后的独立危险因素(OR=6.379、0.033、66.678、0.014、0.094,P 均＜0.050,95%CI:1.380 ～29.482、0.002 ～0.598、5.433 ～818.294、0.001 ～0.183、0.012 ～0.724),Angptl 3 和Angptl 4 蛋白表达不是影响浸润性乳腺癌患者预后的独立因素(OR=1.262、1.841,P=0.937、0.695,95%CI:0.000 ～2.281、0.087 ～39.051)。

结论

Angptl 3 和Angptl 4 在浸润性乳腺癌中高表达,且两者呈正相关。 两者阳性表达的患者生存期缩短,但两者均不是影响浸润性乳腺癌患者预后的独立因素。

关键词: 乳腺肿瘤, 血管生成素类, 免疫组织化学, 预后

Objective

To detect the expressions of angiopoietin-like proteins (Angptl) 3 and Angptl 4 in invasive breast cancer and the clinical significance, and explore the potentials as biomarkers for the treatment and prognosis of breast cancer.

Methods

The tumor samples surgically resected from 70 cases of invasive breast cancer and 30 cases of breast fibroadenoma in Subei People's Hospital from 2007 to 2009 were collected to determine the expressions of Angptl 3 and Angptl 4 with immunohistochemical SP method. χ2 test was used to analyze the expression difference of these two proteins between invasive breast cancer and breast fibroadenoma.χ2 test and Fisher's exact probability method were used to analyze the relationship between the protein expression and clinicopathological characteristics of invasive breast cancer. Spearman correlation analysis was used to detect the correlation between Angptl 3 and Angptl 4 in invasive breast cancer. Kaplan-Meier method and Cox model were used for survival analysis.

Results

The positive rate of Angptl 3 was 75.7%(53/70)in invasive breast cancer and 46.7% (14/30)in breast fibroadenoma (χ2 = 8.014, P=0.005); the positive rate of Angptl 4 was 68.6%(48/70)in invasive breast cancer and 36.7%(11/30)in breast fibroadenoma (χ2=8.837, P=0.003), both indicating a significant difference. In 70 cases of invasive breast cancer, Angptl 3 expression showed a significant difference in patients with different tumor size, axillary lymph node metastasis, TNM stage and ER status(χ2=6.000, 5.598, 9.714, 8.753,P＜0.050); Angptl 4 expression showed a significant difference in patients with different tumor size, axillary lymph node metastasis and TNM stage (χ2=8.762,6.526,5.701, P＜0.050); Angptl 3 was positively correlated with Angptl 4(P=0.005, r=0.334). Kaplan-Meier analysis showed that the survival in patient with Angptl 3 /Angptl 4 positive was superior to that in patient with Angptl 3/Angptl 4 negative (χ2=9.376,7.628;P=0.002,0.006). Cox multivariate survival analysis showed that age, histological grade, tumor size, ER and PR status were independent risk factors in prognosis of invasive breast patients (OR=6.379,0.033,66.678,0.014,0.094;all P＜0.050;95%CI:1.380-29.482,0.002-0.598,5.433-818.294,0.001-0.183,0.012-0.724), while Angptl 3 and Angptl 4 expressions were not (OR=1.262,1.841;P=0.937,0.695; 95%CI:0.000-2.281,0.087-39.051).

Conclusions

Angptl 3 and Angptl 4 are highly expressed in invasive breast cancer, with a positive correlation. The patients with Angptl 3 and Angptl 4 positive have a short survival,however the two are not the independent risk factors in the prognosis of invasive breast caner patients.

Key words: Breast neoplasms, Angiopoietins, Immunohistochemistry, Prognosis
表1 浸润性乳腺癌患者预后相关因素赋值表
变量 赋值
年龄 ＜50岁=0;≥50岁=1
组织学分级 1级=0;2、3级=1
淋巴结转移 无转移=0;有转移=1
肿瘤直径 ≤2 cm=0;＞2 cm=1
ER 阳性=0;阴性=1
PR 阳性=0;阴性=1
HER-2 阳性=0;阴性=1
TNM分期 Ⅰ、Ⅱ期=0;Ⅲ、Ⅳ期=1
Angptl 3 阳性=0;阴性=1
Angptl 4 阳性=0;阴性=1
生存时间 连续变量
生存结局 死亡=0;删失=1
表2 乳腺癌患者临床病理特征与Angptl 3 和Angptl 4 表达之间的关系
临床病理特征 例数 Angptl 3 χ2值 P值 Angptl 4 χ2值 P值
+ - + -
发病年龄
＜50岁 30 24 6 0.524 0.469 22 8 0.552 0.459
≥50岁 40 29 11 26 14
肿瘤直径
≤2 cm 24 14 10 6.000 0.014 11 13 8.762 0.003
＞2 cm 46 39 7 37 9
腋窝淋巴结转移
无 32 20 12 5.598 0.018 17 15 6.526 0.011
有 38 33 5 31 7
组织学分级
1级 23 17 6 0.060 0.806 16 7 0.016 0.900
2、3级 47 36 11 32 15
TNM分期
Ⅰ、Ⅱ期 27 15 12 9.714 0.002 14 13 5.701 0.017
Ⅲ、Ⅳ期 43 38 5 34 9
病理类型
导管癌 43 36 7 4.100a 0.110a 33 10 3.606a 0.179a
髓样癌 13 8 5 7 6
小叶癌 14 9 5 8 6
ER
+ 42 37 5 8.753 0.003 29 13 0.011 0.916
- 28 16 12 19 9
PR
+ 35 30 5 3.807 0.051 25 10 0.265 0.607
- 35 23 12 23 12
HER-2
+ 21 16 5 0.004 0.951 15 6 0.114 0.736
- 49 37 12 33 16
表3 乳腺癌中Amgptl 3 与Angptl 4 表达的相关性分析
Angptl 3 Angptl 4 合计
+ -
+ 41 12 53
- 7 10 17
合计 48 22 60
图1 70 例浸润性乳腺癌患者的Angptl 3 表达与OS 的关系 注:χ2=9.376,P=0.002
图2 70 例浸润性乳腺癌患者的Angptl 4 表达与OS 的关系 注:χ2=7.628,P=0.006
表4 乳腺癌患者的Cox 多因素生存分析
变量 B值 标准误 Wald值 P值 OR值 95%CI
年龄 1.853 0.781 5.630 0.018 6.379 1.380～29.482
组织学分级 -3.400 1.472 5.331 0.021 0.033 0.002～0.598
肿瘤直径 4.200 1.279 10.778 0.001 66.678 5.433～818.294
ER -4.255 1.304 10.657 0.001 0.014 0.001～0.183
PR -2.364 1.042 5.150 0.023 0.094 0.012～0.724
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