High-level Coexpression of JAG1 and NOTCH1 Is Observed in Human Breast Cancer and Is Associated with Poor Overall Survival

Abstract

Aberrant activation of Notch receptors has been shown to cause mammary tumors in mice. We therefore used in situ hybridization to analyze expression of Notch ligands and receptors in human breast cancer. High levels of JAG1 and NOTCH1 were noted in a subset of tumors with poor prognosis pathologic features (P < 0.05). We therefore used tissue microarrays to analyze the expression of these genes in a collection of breast cancers from patients representing a wide spectrum of clinical stages, and from whom associated followup survival data was available (n = 184). Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes [5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1Hi vs. Lo (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1Hi vs. Lo (P = 0.02)]. Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). These data (a) identify novel prognostic markers for breast cancer, (b) suggest a mechanism whereby Notch is activated in aggressive breast tumors, and (c) may identify a signaling pathway activated in poor prognosis breast cancer which can be therapeutically targeted. (Cancer Res 2005; 65(18): 8530-37)

Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

“…Jagged-1 has been found to be up-regulated in prostate 11 and some other cancers such as glioma and breast cancer. 14,15 Surprisingly, in the current study, we found that the knockdown of Jagged-1 exerts a much stronger growth inhibitory effect on prostate cancer cells compared to Notch-1 knockdown. This could be due to down-regulation of Jagged-1 along downregulation of the activity of other Notch family members, such as Notch-2.…”

A Monoclonal Antibody against Human Notch1 Ligand–Binding Domain Depletes Subpopulation of Putative Breast Cancer Stem–like Cells

“…S8). Overexpression of Notch receptors and ligands and consequent increase in Notch activity has been reported in number of cancers, particularly the breast cancer and their early precursors, linking upregulated Notch signaling to pathogenesis (15,43,46). Therefore, several attempts have been made to inhibit Notch function by small-molecular inhibitors such as GSIs or short interfering RNAmediated approaches.…”

“…Several studies suggest that Notch receptor and ligands are overexpressed in the breast cancer tissues compared with the normal breast epithelium (14,27,43,44) and there is a strong correlation between high expression of Notch1 and Jagged1 and poor prognosis and survival (15). Because mAb 602.101 inhibited Jagged1 and Delta-like4 activities in the Notch1-overexpressing cells, ability of this antibody to inhibit Notch signaling in the cancer cell lines MCF-7 and MDA-MB-231 was investigated.…”

“…Both overexpression and downregulation of Notch receptors and ligands have been implicated in human cancers (9)(10)(11)(12). Many reports suggest a strong correlation between coexpression of Notch receptors and its ligands in the breast cancer pathogenesis, which in turn leads to poor prognosis and survival in different cohorts (13)(14)(15)(16)(17). Recent studies have suggested presence of cancer stem cell (CSC) subpopulation in various cancerous tissues including breast cancers (18).…”

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

“…Reedijk et al(2005) found that the expression of each member of the Notch gene family could be detected to varying degrees in a survey of 184 breast carcinomas. In fact, high levels of Notch1 and its ligand JAG1 were linked to poor overall survival.…”