Notch signaling defines an evolutionarily conserved cell interaction mechanism that broadly controls cell fate acquisition in metazoans and consequently, profoundly affects cellular differentiation, apoptosis and proliferation. In humans, Notch signaling abnormalities have been linked to a variety of pathogenic conditions and its involvement in carcinogenesis is being increasingly appreciated, thus Notch has become an important potential target for cancer therapy. We propose to explore specific models and unique transgenic reagents we developed which now allow us to address systematically the fundamental question of Notch signal integration at the cellular level, and in particular, how it relates to the synergy of Notch signals with other cellular elements to influence, cause or sustain oncogenesis in the mammary epithelium.

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Our work directly addresses the link between Notch signaling and tumorigenesis in the mammary gland. We are taking advantage of novel transgenic mice we generated to study the effects of Notch signals in the mammary epithelium, while we also use Drosophila Genetics as a powerful tool to examine how Notch signals integrate their action with other cellular elements to affect cell proliferation. Our goal is to gain insights into the involvement of Notch signaling in cell proliferation and consequently its involvement in breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Yassin, Rihab R,
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Harvard University
Anatomy/Cell Biology
Schools of Medicine
United States
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Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2014) Genetic circuitry modulating notch signals through endosomal trafficking. Methods Enzymol 534:283-99
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2013) Notch signaling at a glance. J Cell Sci 126:2135-40
Fleming, Robert J; Hori, Kazuya; Sen, Anindya et al. (2013) An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling. Development 140:2039-49
Oh, Philmo; Lobry, Camille; Gao, Jie et al. (2013) In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell 13:190-204
Sale, Sanja; Lafkas, Daniel; Artavanis-Tsakonas, Spyros (2013) Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15:451-60
Sun, Youping; Klauzinska, Malgorzata; Lake, Robert J et al. (2011) Trp53 regulates Notch 4 signaling through Mdm2. J Cell Sci 124:1067-76
Fre, Silvia; Hannezo, Edouard; Sale, Sanja et al. (2011) Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One 6:e25785
Arboleda-Velasquez, Joseph F; Manent, Jan; Lee, Jeong Hyun et al. (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108:E128-35
Hori, Kazuya; Sen, Anindya; Kirchhausen, Tom et al. (2011) Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol 195:1005-15
Mazzone, Marco; Selfors, Laura M; Albeck, John et al. (2010) Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A 107:5012-7

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