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

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.

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

“…Moreover, these tumors were focal and rarely involved more than one breast, whereas the invasive carcinomas in control animals were multifocal and involved several mammary glands, as reported in ref. 12.…”

“…Moreover, the proliferative potential of cells derived from such tumors was dramatically suppressed by pharmacological inhibition of Notch1 (9). In addition to these correlations, compelling evidence for tumorigenic action of Notch in the mammary epithelium has been derived from animal studies (10)(11)(12).…”

“…Previously, we generated a mouse model in which all mammary glands of transgenic females expressing a constitutively active Notch1 IC (N1 IC ) transgene driven by the mouse mammary tumor virus (MMTV) LTR develop lactation-dependent papillary tumors that are noninvasive and regress upon gland involution (12). After additional pregnancies, however, multifocal invasive (nonregressing) tumors also appear, apparently evolving from remnants of N1 IC -induced in situ neoplasms through the occurrence of secondary tumorigenic events.…”

Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

“…Fan et al (2004) also showed that Notch1ICD and Notch2ICD can have opposite effects on the growth of a single tumor type. Moreover, Notch1 acts as an oncogene in some carcinomas (Capobianco et al, 1997;Weijzen et al, 2002;Kiaris et al, 2004), and as a tumor suppressor (Nicolas et al, 2003;Fan et al, 2004) in others. Our results taken together with these are consistent with the conclusion that the Nocth effect on TGF-b signaling is cell line-dependent and Notchdependent.…”

“…The Notch4 promoter (but not Notch2 or Notch3) like Hes1 contains CSL-binding elements and therefore, is also a target gene of Notch1 (Weijzen et al, 2002). Genetic alterations of Notch1 or Notch4 that lead to the deregulated expression of the Notch ICD represent gain of function mutations that are associated with T-lymphoblastic and mammary tumorigenesis, respectively (Ellisen et al, 1991;Jhappan et al, 1992;Zagouras et al, 1995;Gallahan et al, 1996;Kiaris et al, 2004).…”