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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098402-10
Application #
8271419
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Yassin, Rihab R,
Project Start
2003-06-18
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$357,272
Indirect Cost
$146,492
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Ho, Diana M; Pallavi, S K; Artavanis-Tsakonas, Spyros (2015) The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis. Elife 4:e05996
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2014) Genetic circuitry modulating notch signals through endosomal trafficking. Methods Enzymol 534:283-99
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
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2013) Notch signaling at a glance. J Cell Sci 126:2135-40
Å ale, Sanja; Lafkas, Daniel; Artavanis-Tsakonas, Spyros (2013) Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15:451-60
Hori, Kazuya; Sen, Anindya; Kirchhausen, Tom et al. (2012) Regulation of ligand-independent Notch signal through intracellular trafficking. Commun Integr Biol 5:374-6
Guruharsha, K G; Kankel, Mark W; Artavanis-Tsakonas, Spyros (2012) The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13:654-66
Louvi, Angeliki; Artavanis-Tsakonas, Spyros (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23:473-80
Pallavi, S K; Ho, Diana M; Hicks, Chindo et al. (2012) Notch and Mef2 synergize to promote proliferation and metastasis through JNK signal activation in Drosophila. EMBO J 31:2895-907

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