Colbert Laronna S, Wilson Kaamilah, Kim Sungjin, Liu Yuan, Oprea-Ilies Gabriela, Gillespie Corey, Dickson Toi, Newman Gale, Gonzalez-Perez Ruben Rene
Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
BMC Cancer. 2014 Apr 9;14:249. doi: 10.1186/1471-2407-14-249.
Notch, IL-1 and leptin are known pro-angiogenic factors linked to breast cancer development, tumor aggressiveness and poor prognosis. A complex crosstalk between these molecules (NILCO) has been reported in breast cancer cell lines. However, whether NILCO biomarkers are differentially expressed in estrogen responsive (ER+), unresponsive (ER-) and triple negative (TNBC) breast cancer tissues is unknown.
Expression levels of nine NILCO and targets [Notch1, Notch4, JAG1, DLL4, VEGF, VEGFR2 (FLK-1), leptin, leptin receptor (OB-R) and interleukin-1 receptor type I (IL-1R tI)] were examined via immunohistochemistry in breast cancer tissue microarrays from Chinese patients (ER+, n=33; ER-, n=21; TNBC, n=13) and non-malignant breast tissue (n=5; Pantomics, Inc.) using a semi-quantitative analysis of intensity staining, HSCORE.
Categorical expression of NILCO and targets (+ or -) was similar among all cancer tissues. However, TNBC showed differential localization pattern of NILCO. TNBC showed fewer nuclei and cytoplasms positive for Notch4 and JAG1, but more cytoplasms positive for leptin. In addition, fewer TNBC stromas were positive for Notch1 and Notch4, but 100% of TNBC stromas were positive for VEGFR2. Moreover, TNBC had lower DLL4 and IL-1R tI expression. TNBC and ER- showed higher expression of EGFR, but lower expression of AR. Leptin and OB-R were detected in more than 61% of samples. Leptin positively correlated to OB-R, JAG1, VEGF, and marginally to IL-1R tI. Notch1 positively correlated to IL-1R tI. EGFR and Ki67 were positively associated to Notch1, but no associations of NILCO and targets with p53 were found.
Present data suggest that NILCO components are differentially expressed in breast cancer. TNBC showed distinctive patterns for NILCO expression and localization. The complex crosstalk between leptin, IL-1 and Notch could differentially drive breast cancer growth and angiogenesis. Furthermore, the analysis of NILCO and targets using Pathway Studio9 software (Ariadine Genomics) showed multiple molecular relationships that suggest NILCO has potential prognostic biomarker value in breast cancer.
Notch、白细胞介素-1（IL-1）和瘦素是已知的促血管生成因子，与乳腺癌的发生发展、肿瘤侵袭性及不良预后相关。在乳腺癌细胞系中已报道了这些分子之间存在复杂的相互作用（NILCO）。然而，NILCO生物标志物在雌激素反应性（ER+）、无反应性（ER-）和三阴性（TNBC）乳腺癌组织中是否存在差异表达尚不清楚。
通过免疫组织化学检测了来自中国患者的乳腺癌组织芯片（ER+，n = 33；ER-，n = 21；TNBC，n = 13）和非恶性乳腺组织（n = 5；Pantomics公司）中9种NILCO及其靶点[Notch1、Notch4、JAG1、DLL4、血管内皮生长因子（VEGF）、血管内皮生长因子受体2（VEGFR2，即FLK-1）、瘦素、瘦素受体（OB-R）和白细胞介素-1 I型受体（IL-1R tI）]的表达水平，采用强度染色半定量分析方法HSCORE进行检测。
所有癌组织中NILCO及其靶点的分类表达（阳性或阴性）相似。然而，TNBC显示出NILCO不同的定位模式。TNBC中Notch4和JAG1阳性的细胞核和细胞质较少，但瘦素阳性的细胞质较多。此外，TNBC基质中Notch1和Notch4阳性较少，但100%的TNBC基质VEGFR2阳性。而且，TNBC中DLL4和IL-1R tI表达较低。TNBC和ER-中表皮生长因子受体（EGFR）表达较高，但雄激素受体（AR）表达较低。超过61%的样本中检测到瘦素和OB-R。瘦素与OB-R、JAG1、VEGF呈正相关，与IL-1R tI呈微弱正相关。Notch1与IL-1R tI呈正相关。EGFR和Ki67与Notch1呈正相关，但未发现NILCO及其靶点与p53存在关联。
现有数据表明NILCO成分在乳腺癌中存在差异表达。TNBC显示出NILCO表达和定位的独特模式。瘦素、IL-1和Notch之间复杂的相互作用可能以不同方式驱动乳腺癌的生长和血管生成。此外，使用Pathway Studio9软件（Ariadine Genomics）对NILCO及其靶点进行分析显示了多种分子关系，提示NILCO在乳腺癌中具有潜在的预后生物标志物价值。
