Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins.
Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins.
复制标题
DOI：
10.1186/1471-2407-14-781
复制
发表时间：
2014-10-24
期刊：
影响因子：
3.8
通讯作者：
Cheng N
中科院分区：
文献类型：
--
作者：
Zou A;Lambert D;Yeh H;Yasukawa K;Behbod F;Fan F;Cheng N
CXCL 1是一种趋化性细胞因子，可调节乳腺癌的进展和化疗耐药性。然而，CXCL 1在乳腺癌中表达的预后意义尚未得到充分的表征。成纤维细胞是乳腺肿瘤微环境的重要细胞成分，最近的研究表明，这种细胞类型是乳腺肿瘤中CXCL 1表达的潜在来源。本研究的目的是进一步表征乳腺癌间质中CXCL 1的表达模式，确定间质CXCL 1表达的预后意义，并确定影响间质CXCL 1表达的因素。采用免疫组化方法检测54例正常乳腺组织和83例乳腺癌组织中CXCL 1蛋白的表达。通过http://www.Oncomine.org数据挖掘分析乳腺癌间质中CXCL 1的RNA表达，并通过单因素分析CXCL 1表达与预后因素的关系。采用免疫荧光共染色法检测成纤维细胞中CXCL 1、α-平滑肌肌动蛋白（α-SMA）和成纤维细胞特异性蛋白1（FSP 1）的表达。通过候选人分析，TGF-β信号通路被鉴定为成纤维细胞中CXCL 1表达的调节因子。采用免疫组化和数据挖掘分析TGF-β和SMAD基因产物的表达。单因素分析基质CXCL 1与TGF-β信号组分的关系。用重组TGF-β处理从MMTV-PyVmT乳腺肿瘤分离的癌相关成纤维细胞，并通过荧光素酶测定分析CXCL 1启动子活性，通过ELISA分析蛋白分泌。乳腺癌间质中CXCL 1表达升高与肿瘤分级、疾病复发和患者生存率降低相关。免疫荧光共染色显示CXCL 1与α-SMA和FSP 1蛋白表达重叠。间质CXCL 1蛋白表达与TGF-β信号成分表达呈负相关。用TGF-β处理成纤维细胞抑制CXCL 1分泌和启动子活性。乳腺癌间质中CXCL 1表达增加与患者预后不良相关。此外，CXCL 1表达定位于α-SMA和FSP 1阳性成纤维细胞，并受TGF-β信号负调控。这些研究表明，癌相关成纤维细胞中TGF-β信号转导的减少增强了成纤维细胞中CXCL 1的表达，这可能有助于乳腺癌的进展。本文的在线版本（doi：10.1186/1471-2407-14-781）包含补充材料，可供授权用户使用。
CXCL1 is a chemotactic cytokine shown to regulate breast cancer progression and chemo-resistance. However, the prognostic significance of CXCL1 expression in breast cancer has not been fully characterized. Fibroblasts are important cellular components of the breast tumor microenvironment, and recent studies indicate that this cell type is a potential source of CXCL1 expression in breast tumors. The goal of this study was to further characterize the expression patterns of CXCL1 in breast cancer stroma, determine the prognostic significance of stromal CXCL1 expression, and identify factors affecting stromal CXCL1 expression. Stromal CXCL1 protein expression was analyzed in 54 normal and 83 breast carcinomas by immunohistochemistry staining. RNA expression of CXCL1 in breast cancer stroma was analyzed through data mining in http://www.Oncomine.org. The relationships between CXCL1 expression and prognostic factors were analyzed by univariate analysis. Co-immunofluorescence staining for CXCL1, α-Smooth Muscle Actin (α-SMA) and Fibroblast Specific Protein 1 (FSP1) expression was performed to analyze expression of CXCL1 in fibroblasts. By candidate profiling, the TGF-β signaling pathway was identified as a regulator of CXCL1 expression in fibroblasts. Expression of TGF-β and SMAD gene products were analyzed by immunohistochemistry and data mining analysis. The relationships between stromal CXCL1 and TGF-β signaling components were analyzed by univariate analysis. Carcinoma associated fibroblasts isolated from MMTV-PyVmT mammary tumors were treated with recombinant TGF-β and analyzed for CXCL1 promoter activity by luciferase assay, and protein secretion by ELISA. Elevated CXCL1 expression in breast cancer stroma correlated with tumor grade, disease recurrence and decreased patient survival. By co-immunofluorescence staining, CXCL1 expression overlapped with expression of α-SMA and FSP1 proteins. Expression of stromal CXCL1 protein expression inversely correlated with expression of TGF-β signaling components. Treatment of fibroblasts with TGF-β suppressed CXCL1 secretion and promoter activity. Increased CXCL1 expression in breast cancer stroma correlates with poor patient prognosis. Furthermore, CXCL1 expression is localized to α-SMA and FSP1 positive fibroblasts, and is negatively regulated by TGF-β signaling. These studies indicate that decreased TGF-β signaling in carcinoma associated fibroblasts enhances CXCL1 expression in fibroblasts, which could contribute to breast cancer progression. The online version of this article (doi:10.1186/1471-2407-14-781) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
7.3
作者：
Bombonati, Alessandro;Sgroi, Dennis C.
通讯作者：
Sgroi, Dennis C.
影响因子：
3.8
作者：
Figueroa JD;Flanders KC;Garcia-Closas M;Anderson WF;Yang XR;Matsuno RK;Duggan MA;Pfeiffer RM;Ooshima A;Cornelison R;Gierach GL;Brinton LA;Lissowska J;Peplonska B;Wakefield LM;Sherman ME
通讯作者：
Sherman ME
影响因子：
10.3
作者：
Brennen, W. Nathaniel;Rosen, D. Marc;Denmeade, Samuel R.
通讯作者：
Denmeade, Samuel R.
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
4.4
作者：
Brodmerkel, CM;Huber, R;Vaddi, K
通讯作者：
Vaddi, K