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Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers.

间质中趋化因子C-C配体2表达升高与基底细胞样乳腺癌复发有关

Yao M,Yu E,Staggs V,Fan F,Cheng N

Abstract

Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal-like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n=427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR=7.51 P=0.007) was associated with a greater hazard than cancer stage (HR=2.45, P=0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis.

摘要

尽管治疗上有进步,但是多达30%的乳腺癌患者会出现侵袭性更强和预后更差的疾病复发。乳腺癌的治疗由于有多个亚型而比较复杂,包括:管腔型、Her2过表达型、侵袭性基底细胞样乳腺癌确定乳腺癌亚型的新型特异性标志物,可以有助于对患者预后的预测并有助于改进治疗策略。微环境通过生长因子、血管生成因子、其他可溶性蛋白质的表达影响乳腺癌进展。特别是趋化因子C-C配体2调节原发性肿瘤的巨噬细胞聚集并调节癌细胞信号来促进乳腺肿瘤进展。

我们基于软件来评估乳腺癌亚型中CCL2蛋白表达的预后意义,评估CCL2在上皮细胞或基质中的表达与间质标记物--纤维母细胞特异性蛋白1(Fsp1)的关系。组织芯片免疫组织化学结果表明,在浸润性导管癌的间质和肿瘤上皮细胞中,CCL2与Fsp1表达密切相关。在浸润性导管癌(n=427),CCL2和Fsp1在组织、间质和上皮细胞中的表达与癌症分期和肿瘤大小成负相关。关于分子亚型,间质CCL2在基底细胞样乳腺癌中表达最强。Cox回归分析表明,间质CCL2(而不是上皮细胞CCL2)表达与无瘤生存率降低密切相关。此外,在多变量分析中,间质CCL2(HR=7.51 P=0.007)表达比癌症分期(HR=2.45 P=0.048)风险更大。

这些研究表明,间质CCL2与基底细胞样乳腺癌患者的无瘤生存率降低相关,尤其对于使用间质标记物预测患者预后有重要意义。

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