Wong Sze Chuen Cesar, Lo Siu Fong Elena, Lee King Chung, Yam Judy W P, Chan John K C, Wendy Hsiao W L
Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China.
J Pathol. 2002 Feb;196(2):145-53. doi: 10.1002/path.1035.
Frizzled-related protein (Frp) is a new family of secreted proteins that contain a region homologous to the extracellular cysteine-rich domain (CRD) of the frizzled family proteins. The role of Frp protein is far from clear. To explore the role of Frp and its relationship to the Wnt-signalling pathway in breast cancer, in situ hybridization and immunohistochemical analyses of Frp, Wnt-1, APC, beta-catenin, and its target genes c-myc and cyclin D1 were conducted in 70 specimens of invasive ductal carcinomas of the human breast. Frp mRNA was down-regulated in 62 and elevated in eight tumour specimens, compared with adjacent normal tissues. In the course of tumour progression, however, Frp mRNA steadily increased in both tumour and the adjacent tissues. Interestingly, the number of cases with axillary lymph node metastasis was significantly lower in the group with elevated Frp than in the group with decreased Frp, suggesting that Frp may contribute as a prognostic factor in invasive breast cancer. Wnt-1, a gene implicated in human breast cancer, was markedly elevated in grade 1 tumours, but declined as tumour grade declined. The level of Wnt-1 was linearly correlated with its downstream target beta-catenin (p<0.05), but was inversely correlated with Frp (p<0.05), suggesting a possible negative regulatory role of Frp with regard to Wnt-1. APC was inversely correlated with beta-catenin (p<0.05). Beta-catenin, a key transcriptional activator responsible for the activation of both c-myc and cyclin D1 in colorectal tumours, was detected at high levels in the plasma membranes of cells in normal tissue. In tumour masses, however, beta-catenin lost its tight association with the membrane and diffused into the cytoplasm. Surprisingly, it clearly did not penetrate the nuclei, despite the fact that both c-myc and cyclin D1 were markedly elevated in all tumour tissues. As revealed in this study, Wnt-1/beta-catenin plays very different roles in the oncogenesis of breast and colon cancers. This first systemic analysis of the Frp and the Wnt-signalling pathway in human breast cancer provides a springboard for further work on the role of Frp in the development of breast cancer.
卷曲相关蛋白（Frp）是一类新的分泌蛋白家族，其包含一个与卷曲蛋白家族蛋白的细胞外富含半胱氨酸结构域（CRD）同源的区域。Frp蛋白的作用尚不清楚。为了探究Frp在乳腺癌中的作用及其与Wnt信号通路的关系，对70例人乳腺浸润性导管癌标本进行了Frp、Wnt-1、APC、β-连环蛋白及其靶基因c-myc和细胞周期蛋白D1的原位杂交和免疫组化分析。与相邻正常组织相比，62例肿瘤标本中Frp mRNA表达下调，8例肿瘤标本中Frp mRNA表达上调。然而，在肿瘤进展过程中，肿瘤组织和相邻组织中的Frp mRNA均稳步增加。有趣的是，Frp升高组的腋窝淋巴结转移病例数明显低于Frp降低组，这表明Frp可能作为浸润性乳腺癌的一个预后因素。Wnt-1是一种与人类乳腺癌相关的基因，在1级肿瘤中显著升高，但随着肿瘤分级降低而下降。Wnt-1水平与其下游靶标β-连环蛋白呈线性相关（p<0.05），但与Frp呈负相关（p<0.05），提示Frp对Wnt-1可能具有负调控作用。APC与β-连环蛋白呈负相关（p<0.05）。β-连环蛋白是一种关键的转录激活因子，负责在结直肠癌中激活c-myc和细胞周期蛋白D1，在正常组织细胞的质膜中高水平表达。然而，在肿瘤块中，β-连环蛋白失去了与膜的紧密结合并扩散到细胞质中。令人惊讶的是，尽管所有肿瘤组织中c-myc和细胞周期蛋白D1均显著升高，但β-连环蛋白显然未进入细胞核。如本研究所示，Wnt-1/β-连环蛋白在乳腺癌和结肠癌的肿瘤发生中发挥着非常不同的作用。对人乳腺癌中Frp和Wnt信号通路的首次系统分析为进一步研究Frp在乳腺癌发生中的作用提供了一个跳板。
