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(American Journal of Pathology. 2004;165:695-705.)
© 2004 American Society for Investigative Pathology

Animal Models

Modulation of Notch Signaling Elicits Signature Tumors and Inhibits Hras1-Induced Oncogenesis in the Mouse Mammary Epithelium

Hippokratis Kiaris*, Katerina Politi{dagger}, Lisa M. Grimm*, Matthias Szabolcs{ddagger}, Peter Fisher{ddagger}, Argiris Efstratiadis{dagger}§ and Spyros Artavanis-Tsakonas*¶

From the Department of Cell Biology,* Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts; the Departments of Genetics and Development{dagger} and Pathology,{ddagger} and the Institute for Cancer Genetics,§ Columbia University, New York, New York; and the Collège de France, Paris, France

Abstract

Deregulation of Notch signaling, which normally affects a broad spectrum of cell fates, has been implicated in various neoplastic conditions. Here we describe a transgenic mouse model, which demonstrates that expression of a constitutively active form of the Notch1 receptor in the mammary epithelium induces the rapid development of pregnancy/lactation-dependent neoplasms that consistently exhibit a characteristic histopathological pattern. These signature tumors retain the ability to respond to apoptotic stimuli and regress on initiation of mammary gland involution, but eventually appear to progress in subsequent pregnancies to nonregressing malignant adenocarcinomas. Additionally, we present evidence indicating that cyclin D1 is an in vivo target of Notch signals in the mammary glands and demonstrate that we can effectively inhibit Hras1-driven, cyclin D1-dependent mammary oncogenesis by transgenic expression of the Notch antagonist Deltex.




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