title: 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 Notch1/Myc 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.
authors.affiliation: Department of Genetics and Development, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Hippokratis
authors.initials: H
authors.lastname: Kiaris
authors.forename: Spyros
authors.initials: S
authors.lastname: Artavanis-Tsakonas
authors.forename: Argiris
authors.initials: A
authors.lastname: Efstratiadis
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D014158:Transcription, Genetic
chemical_list: C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1