Zhang Gui-hong, Yang Wen-tao, Zhou Xiao-yan, Zeng Yu, Lu Hong-fen, Shi Da-ren
Department of Pathology, Cancer Hospital, Fudan University, Shanghai 200032, China.
Zhonghua Yi Xue Za Zhi. 2007 Jan 16;87(3):155-60.
To demonstrate the molecular mechanism of poor prognosis in HER-2 overexpressing breast carcinoma, to study the correlation between angiogenesis/lymphangiogenesis and HER-2, and the effect of them in the progression and prognosis, so as to provide novel molecular markers for lymph node metastasis and prognosis in breast carcinoma.
(1) By using TaqMan real-time quantitative reverse transcription polymerase chain reaction (real-time qRT-PCR) technique and immunohistochemistry (IHC), the mRNA and protein expression of VEGF-C were detected in SKBR-3 and MDA-MB-231 cell lines before and after the interference with Herceptin. (2) Real-time qRT-PCR was performed to detect the mRNA expression of VEGF-C and -D genes in 67 cases of primary breast infiltrating ductal carcinoma. (3) 160 formalin-fixed paraffin-embedded infiltrating ductal carcinomas were selected. The protein expression of HER-2, VEGF-C, lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) were detected by IHC.
(1) After interference with Herceptin, the VEGF-C mRNA and protein expression of sKBR-3 the cells decreased significantly. In primary breast cancer, the protein expression of HER-2 was positively correlated with VEGF-C protein expression (r = 0.215, P < 0.05). There was a significantly positive correlation between VEGF-C protein expression and LVD (r = 0.248, P < 0.01). (2) VEGF-C mRNA expression in the patients with lymph node metastasis was higher than that in the patients without lymph node metastasis (1.6 +/- 0.5 vs 1.1 +/- 0.5) (t = 2.196, P < 0.05). Logistic regression model showed HER-2, LVD and LVI were important factors influencing lymph node metastasis (all P < 0.05). (3) Kaplan-Meier analysis indicated that HER-2 protein overexpression, VEGF-C protein overexpression, and high LVD and LVI were associated with patient's worse disease-free survival (P(uni) < 0.05). Cox regression analysis indicated that HER-2 and LVI were the independent prognostic factors of breast cancer (both P(mult) < 0.05).
Through up-regulating VEGF-C expression, HER-2 overexpression induces lymphangiogenesis, promotes metastasis, and results in the poor prognosis of breast cancer. VEGF-C expression, LVD and LVI are novel prognostic indicators of breast cancer.
探讨HER-2过表达乳腺癌预后不良的分子机制，研究血管生成/淋巴管生成与HER-2的相关性及其在肿瘤进展和预后中的作用，为乳腺癌淋巴结转移及预后提供新的分子标志物。
（1）应用TaqMan实时定量逆转录聚合酶链反应（real-time qRT-PCR）技术及免疫组化（IHC）方法，检测赫赛汀干扰前后SKBR-3和MDA-MB-231细胞系中VEGF-C的mRNA和蛋白表达。（2）采用real-time qRT-PCR检测67例原发性乳腺浸润性导管癌中VEGF-C和-D基因的mRNA表达。（3）选取160例甲醛固定石蜡包埋的浸润性导管癌，用IHC检测HER-2、VEGF-C、淋巴管密度（LVD）及淋巴管浸润（LVI）的蛋白表达。
（1）赫赛汀干扰后，SKBR-3细胞的VEGF-C mRNA和蛋白表达明显降低。在原发性乳腺癌中，HER-2蛋白表达与VEGF-C蛋白表达呈正相关（r = 0.215，P < 0.05）。VEGF-C蛋白表达与LVD呈显著正相关（r = 0.248，P < 0.01）。（2）有淋巴结转移患者的VEGF-C mRNA表达高于无淋巴结转移患者（1.6±0.5 vs 1.1±0.5）（t = 2.196，P < 0.05）。Logistic回归模型显示HER-2、LVD和LVI是影响淋巴结转移的重要因素（均P < 0.05）。（3）Kaplan-Meier分析表明，HER-2蛋白过表达、VEGF-C蛋白过表达、高LVD及LVI与患者无病生存期较差相关（P(uni) < 0.05）。Cox回归分析表明，HER-2和LVI是乳腺癌的独立预后因素（均P(mult) < 0.05）。
HER-2过表达通过上调VEGF-C表达诱导淋巴管生成，促进转移，导致乳腺癌预后不良。VEGF-C表达、LVD及LVI是乳腺癌新的预后指标。
