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PMID: 15277242 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium.

The American journal of pathology ·Vol. 165 ·No. 2 ·2004-08-00 ·Pages 695-705

Kiaris H, Politi K, Grimm LM, Szabolcs M, Fisher P, Efstratiadis A, Artavanis-Tsakonas S

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.

MeSH Terms
Adenocarcinoma/pathology Animals Apoptosis Carrier Proteins/metabolism Cell Transformation, Neoplastic/genetics Cyclin D1 Female Gene Expression Regulation, Neoplastic Genes, ras Humans Lactation Male Mammary Glands, Animal/embryology,growth & development Mammary Neoplasms, Animal/genetics,pathology Mammary Tumor Virus, Mouse/genetics,physiology Membrane Proteins/metabolism Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Pregnancy Receptors, Notch Signal Transduction/physiology
Chemicals
Carrier Proteins Membrane Proteins Receptors, Notch deltex protein, vertebrate Cyclin D1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kiaris Hippokratis
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.
Politi Katerina
Grimm Lisa M
Szabolcs Matthias
Fisher Peter
Efstratiadis Argiris
Artavanis-Tsakonas Spyros
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)63333-0
Published
2004-08-00
Pages
695-705
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1618582
Subset
IM
Grants
NCI NIH HHS · CA098402 · United States
NIGMS NIH HHS · GM62931 · United States
NCI NIH HHS · CA97403 · United States
NCI NIH HHS · P01 CA097403 · United States
NINDS NIH HHS · R37 NS026084 · United States
NIGMS NIH HHS · R01 GM062931 · United States
NCI NIH HHS · T32 CA09503 · United States
NCI NIH HHS · T32 CA009503 · United States
NINDS NIH HHS · R01 NS026084 · United States
NCI NIH HHS · R01 CA098402 · United States
NINDS NIH HHS · NS26084 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)63333-0 PMC Full Text View journal details
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