Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium.
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.
Department of Cell Biology, Massachusetts General Hospital Center for Cancer Research, Department of Cell Biology, Harvard Medical School, 13th St., Bldg. 149, Charlestown, MA 02129, USA.
Hippokratis
H
Kiaris
Katerina
K
Politi
Lisa M
LM
Grimm
Matthias
M
Szabolcs
Peter
P
Fisher
Argiris
A
Efstratiadis
Spyros
S
Artavanis-Tsakonas
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019938:Cyclin D1; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007774:Lactation; D008297:Male; D008321:Mammary Glands, Animal / Q000196:embryology / Q000254:growth & development*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*
D002352:Carrier Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C409218:deltex protein, vertebrate; D019938:Cyclin D1