Notch2 Signaling Induces Apoptosis and Inhibits Human MDA-MB-231 Xenograft Growth

Abstract

Notch functions as an oncogene or tumor inhibitor in various cancers, and decreases in Notch2 expressionare associated with increasing grade of human breast cancer. We constitutively activated Notch signaling with intracellular domain (ICD) expression in the human adenocarcinoma line MDA-MB-231. Notch2 signaling increased apoptosis, whereas Notch4ICD (int3) significantly increased cell proliferation and growth. Cells with activated Notch2 or Notch4 were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth was significantly altered depending on the receptor activated. Notch2ICD potently suppressed tumor take and growth, leading to a 60% decrease in tumors and significantly smaller, necrotic tumors. Despite this, Notch2ICD tumors were highly vascularized, although the vessels were smaller and comprised a more immature network compared with Notch4ICD tumors. Notch4ICD tumors were highly aggressive and well vascularized, indicating a role for Notch4 signaling in the promotion of the malignant phenotype in addition to its transforming ability. Although both NotchICD groups expressed angiogenic factors, Notch4ICD had selective vascular endothelial growth factor-D in both tumor and host stroma, suggesting a differential regulation of cytokines that may impact vascular recruitment and autocrine tumor signaling. Our results demonstrate that Notch2 signaling is a potent inhibitory signal in human breast cancer xenografts. (Am J

Soluble Forms of the Notch Ligands Delta1 and Jagged1 Promote in Vivo Tumorigenicity in NIH3T3 Fibroblasts with Distinct Phenotypes

“…34 Over-expression of a constitutively active form of Notch4 in a human adenocarcinoma cell line produced highly aggressive tumors in nude mice in comparison to cells expressing the intracellular domain of Notch2, which displayed tumor suppressor activity. 59 The subsequent activation of downstream effectors resulting from differential Notch/ligand interactions may also reflect tumor phenotype as the expression of Hes1, Hes3, Hey1, and Hey2 have been associated with several neoplasias including metastatic tumors. 60 Since we found differences in the relative expression of the tumors as well as the effectors, it is possible that the phenotypic differences observed within these tumors are directly attributable to the unique balances in specific receptormediated signals generated within the transfectants.…”

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

“…38 As JAG2 and Notch2 were detected to be significantly up-regulated in APC min/ϩ mice. This finding fits with the report that Notch2 is an Hh target 39,40 and might be up-regulated on Shh signaling.…”

Rational targeting of Notch signaling in breast cancer

“…Similarly, constitutively active Notch-1 [17] and Notch-4 [18] transform human mammary epithelial cells in vitro. Interestingly, Notch-2 appears to antagonize signals by the other three homologs in breast cancer cells [19]. In breast cancer clinical specimens, mRNA expression of Notch-1 and Notch ligand Jagged-1 have been shown to correlate strongly with poor prognosis [20,21].…”