Sun Baocun, Zhang Shiwu, Zhang Danfang, Li Yan, Zhao Xiulan, Luo Ye, Guo Yuhong
Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, People's Republic of China.
Clin Cancer Res. 2008 Nov 1;14(21):7050-9. doi: 10.1158/1078-0432.CCR-08-0520.
Currently, there are no definite biomarkers of triple-negative breast cancer. The study aims to identify the metastasis-associated proteins of triple-negative breast tumors.
A murine metastatic breast cancer model has been established by using TA2 mice. Parallel proteomic analyses were done on a murine metastatic breast cancer model and its primary breast cancer using two-dimensional gel electrophoresis. The differentially expressed proteins were detected in TA2 mice developing spontaneous breast cancer and lung metastasis. Furthermore, their expression were detected in human breast cancer with or without metastasis, and their prediction values were assessed in a second set of samples.
Nineteen of 36 differentially expressed proteins were identified by peptide mass fingerprinting using matrix-assisted laser-desorption ionization-time of flight-mass spectrometry. These proteins were also validated in mouse tumor tissues by immunohistochemical staining. Actin, 14-3-3, vimentin, HSP70, CK18, and moesin were up-regulated in the metastatic tumors, whereas HSP90 and tubulin were absent or down-regulated. Furthermore, 61 patients with triple-negative breast cancer and 39 patients with estrogen receptor-positive/progesterone receptor-positive breast cancer were selected for exploring the clinical relevance of these identified proteins to human breast cancer metastasis. Expression of 14-3-3 and HSP70 was significantly correlated with metastasis of human triple-negative breast cancer. Moreover, the validation study in the second set confirmed that 14-3-3, HSP70, and their combination had high sensitivities and specificities in predicting metastatic potential of triple-negative breast cancer.
These tumor metastasis-associated proteins validated may be useful as biomarkers and targets for diagnosis and treatment of human triple-negative breast cancer.
目前，三阴性乳腺癌尚无明确的生物标志物。本研究旨在鉴定三阴性乳腺肿瘤的转移相关蛋白。
利用TA2小鼠建立了小鼠转移性乳腺癌模型。采用二维凝胶电泳对小鼠转移性乳腺癌模型及其原发性乳腺癌进行了平行蛋白质组学分析。在发生自发性乳腺癌和肺转移的TA2小鼠中检测差异表达蛋白。此外，检测了其在有无转移的人类乳腺癌中的表达，并在另一组样本中评估了它们的预测价值。
使用基质辅助激光解吸电离飞行时间质谱通过肽质量指纹图谱鉴定了36种差异表达蛋白中的19种。这些蛋白也通过免疫组织化学染色在小鼠肿瘤组织中得到验证。肌动蛋白、14-3-3、波形蛋白、热休克蛋白70（HSP70）、细胞角蛋白18（CK18）和埃兹蛋白在转移性肿瘤中上调，而热休克蛋白90（HSP90）和微管蛋白缺失或下调。此外，选择了61例三阴性乳腺癌患者和39例雌激素受体阳性/孕激素受体阳性乳腺癌患者，以探讨这些鉴定出的蛋白与人类乳腺癌转移的临床相关性。14-3-3和HSP70的表达与人类三阴性乳腺癌的转移显著相关。此外，在另一组中的验证研究证实，14-3-3、HSP70及其组合在预测三阴性乳腺癌转移潜能方面具有高敏感性和特异性。
这些经过验证的肿瘤转移相关蛋白可能作为人类三阴性乳腺癌诊断和治疗的生物标志物及靶点。
