Expression of frizzled‐related protein and Wnt‐signalling molecules in invasive human breast tumours

Abstract

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.

Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt‐1/β‐Catenin Signaling Pathway

“…Accumulated b-catenin can translocate to the nucleus, interact with TCF transcription factors, and thereby mediate transcriptional activation. Wnt-1/b-catenin-mediated transcriptional activation has been implicated in several human malignancies (Wong et al, 2002;Chen et al, 2004). Multiple key oncogenic proteins, including c-Myc, cyclinD1, and Cox-2, have been found to be regulated by the Wnt-1/b-catenin signaling pathway.…”

“…Wnt-1/b-catenin-mediated transcriptional activation has been implicated in several human malignancies such as breast cancer and prostate carcinoma (Wong et al, 2002;Chen et al, 2004). Therefore, we also tested the effect of ING4 overexpression on activation of the Wnt-1/b-catenin signaling pathway and the expression of its target proteins p27, cyclinD1, SKP2, and Cox2 in A549 cells.…”

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…Therefore, targeting Wnt/β-catenin pathway that is responsible for self-renewal can be a potential therapeutics strategy (Woodward et al, 2007). Although mutation of β-catenin may not commonly occurred in human breast cancers, various studies showed the role of Wnt signaling pathway in pathogenesis of breast cancer (Lin et al, 2000;Jain et al, 2002;Wong et al, 2002;Klopocki et al, 2004) suggesting a link between Wnt signaling and DNA damage response in epithelial cells (Ayyanan et al, 2006).…”

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

“…We defined the presence of RacGAP1 expression in the nuclei of cancer cells as positive expression. First, we calculated modified immunohistochemistry (IHC) scores, as described in our previous report [16], by multiplying the percentage of positive epithelial cells (0-100 %) by the staining intensity that was scored as follows: 0, negative; 1, weak; 2, strong. RacGAP1 IHC scores ranged from 0 to 200.…”