Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice

Abstract

To explore the potential involvement of aberrant Notch1 signaling in breast cancer pathogenesis, we have used a transgenic mouse model. In these animals, mouse mammary tumor virus LTR-driven expression of the constitutively active intracellular domain of the Notch1 receptor (N1 IC ) causes development of lactation-dependent mammary tumors that regress upon gland involution but progress to nonregressing, invasive adenocarcinomas in subsequent pregnancies. Up-regulation of Myc in these tumors prompted a genetic investigation of a potential Notch1͞Myc functional relationship in breast carcinogenesis. Conditional ablation of Myc in the mammary epithelium prevented the induction of regressing N1 IC neoplasms and also reduced the incidence of nonregressing carcinomas, which developed with significantly increased latency. Molecular analyses revealed that both the mouse and human Myc genes are direct transcriptional targets of N1 IC acting through its downstream Cbf1 transcriptional effector. Consistent with this mechanistic link, Notch1 and Myc expression is positively correlated by immunostaining in 38% of examined human breast carcinomas.breast cancer ͉ mouse model

NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth

“…4b). These results are in agreement with those of Satoh et al (12), who demonstrated the presence of regulatory elements controlled by Notch1 in the mouse c-Myc promoter, and with recent results by Klinakis et al (13) and Weng et al (14) showing an interaction between Notch1 and c-Myc in mouse breast tumors and leukemia, respectively. Moreover, Western blot analysis showed a gradual reduction of c-MYC protein levels in T-ALL cells after ␥-secretase inhibition (Fig.…”

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

“…The effects of Notch 3 knockdown were identical to the effects of g-secretase inhibition in vitro, namely decreased expression of Notch 3 targets and profound apoptosis. It had been shown previously that Notch signaling can regulate apoptosis (Jhappan et al, 1992;Hu et al, 2006;Klinakis et al, 2006). Results of our in vitro studies were cleaner than our in vivo results that relied on the diffusion of a drug, in this case, GSI-I.…”

Notch1 regulates the functional contribution of RhoC to cervical carcinoma progression

“…Notch1 induces anoikis resistance, inhibits p53 activity and upregulates myc in cervical carcinoma (Rangarajan et al, 2001;Nair et al, 2003;Klinakis et al, 2006;Subramanyam and Krishna, 2006;Weng et al, 2006) and also inhibits the growth inhibitory effects of TGF-b during cell growth (Masuda et al, 2005). Our earlier report suggests that PI3K-mediated EMT in cervical cancer correlates with Jagged1 expression (Veeraraghavalu et al, 2005).…”