de Silva Rudland Suzete, Martin Lee, Roshanlall Chandeene, Winstanley John, Leinster Samuel, Platt-Higgins Angela, Carroll Joe, West Christopher, Barraclough Roger, Rudland Philip
Cancer and Polio Research Fund Laboratories, School of Biological Sciences, Royal Liverpool University Hospital, UK.
Clin Cancer Res. 2006 Feb 15;12(4):1192-200. doi: 10.1158/1078-0432.CCR-05-1580.
S100A4 and the estrogen-inducible osteopontin are alone capable of inducing angiogenesis and metastasis in rodent models for breast cancer. The present study assesses the relationship of S100A4 and osteopontin with vessel density and estrogen receptor alpha (ERalpha) in primary tumors and with survival of patients to ascertain their involvement in metastatic breast cancer.
Primary tumors from 312 patients treated for minimally invasive human breast cancer were immunocytochemically stained and then assessed for the significance of their association with each other using Fisher's exact test or with patient survival over 18 years of follow-up using Kaplan-Meier plots and Wilcoxon-Gehan statistics.
Antibodies to S100A4 significantly stained endothelial cells of vessels adjacent to S100A4-staining groups of carcinoma cells, and antibodies to osteopontin significantly stained groups of carcinoma cells staining for ERalpha (P < 0.0001). There was a significant association of tumors staining for S100A4 with those with high vessel density (P = 0.021) and of tumors staining for osteopontin with those staining for ERalpha (P = 0.034). The association of staining for S100A4, osteopontin, or vessel density with patient death was significant (P < 0.0001, P = 0.005, and P = 0.014, respectively). The difference in cumulative proportion surviving between S100A4-positive patients with higher or lower vessel density increased up to about 12 years, but thereafter decreased to virtually zero after 18 years of follow-up. Patients with both S100A4-positive and osteopontin-positive primary tumors showed a statistically significant reduction in survival time over those with either one alone (P < 0.019), although in multivariate regression analysis, only staining for S100A4 was significant (P < 0.001).
It is suggested that in human breast cancer, S100A4 exerts some of its effects through angiogenesis, and that osteopontin is dependent on ERalpha for its expression.
在乳腺癌啮齿动物模型中，S100A4和雌激素诱导的骨桥蛋白单独就能够诱导血管生成和转移。本研究评估原发性肿瘤中S100A4和骨桥蛋白与血管密度及雌激素受体α（ERα）的关系，以及与患者生存率的关系，以确定它们在转移性乳腺癌中的作用。
对312例接受微创性人类乳腺癌治疗的患者的原发性肿瘤进行免疫细胞化学染色，然后使用Fisher精确检验评估它们彼此之间关联的显著性，或使用Kaplan-Meier图和Wilcoxon-Gehan统计量评估它们与18年随访期患者生存率的关系。
抗S100A4抗体显著标记了与S100A4染色的癌细胞群相邻的血管内皮细胞，抗骨桥蛋白抗体显著标记了ERα染色的癌细胞群（P < 0.0001）。S100A4染色的肿瘤与高血管密度的肿瘤之间存在显著关联（P = 0.021），骨桥蛋白染色的肿瘤与ERα染色的肿瘤之间存在显著关联（P = 0.034）。S100A4、骨桥蛋白或血管密度染色与患者死亡之间的关联显著（分别为P < 0.0001、P = 0.005和P = 0.014）。血管密度较高或较低的S100A4阳性患者之间的累积生存比例差异在约12年时增加，但在18年随访后几乎降至零。S100A4阳性和骨桥蛋白阳性原发性肿瘤患者的生存时间在统计学上显著低于仅有一种阳性的患者（P < 0.019），尽管在多变量回归分析中，只有S100A4染色具有显著性（P < 0.001）。
提示在人类乳腺癌中，S100A4通过血管生成发挥其部分作用，且骨桥蛋白的表达依赖于ERα。
