Downregulation of Notch Pathway by a γ-Secretase Inhibitor Attenuates AKT/Mammalian Target of Rapamycin Signaling and Glucose Uptake in an ERBB2 Transgenic Breast Cancer Model

ERBB2/neu and Notch signaling are known to be deregulated in many human cancers. However, pathway cross-talk and dependencies are not well understood. In this study, we use an ERBB2-transgenic mouse model of breast cancer (neuT) to show that Notch signaling plays a critical role in tumor maintenance...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2010-03, Vol.70 (6), p.2476-2484
Main Authors: EFFERSON, Clay L, WINKELMANN, Christopher T, BUSER, Carolyn, YEATMAN, Timothy, COPPOLA, Domenico, WINTER, Christopher, CLARK, Edwin A, DRAETTA, Giulio F, STRACK, Peter R, MAJUMDER, Pradip K, WARE, Christopher, SULLIVAN, Timothy, GIAMPAOLI, Saverio, TAMMAM, Jennifer, PATEL, Shailendra, MESITI, Giuseppe, REILLY, John F, GIBSON, Raymond E
Format: Article
Language:English
Subjects:
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Animals
Antineoplastic agents
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - enzymology
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cyclic S-Oxides - pharmacology
Down-Regulation - drug effects
Female
Fluorodeoxyglucose F18 - pharmacokinetics
Glucose - pharmacokinetics
Glucose Transporter Type 1 - biosynthesis
Gynecology. Andrology. Obstetrics
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Mammary gland diseases
Mammary Neoplasms, Experimental
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Transgenic
Oncogene Protein v-akt - antagonists & inhibitors
Oncogene Protein v-akt - metabolism
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - metabolism
Protein-Serine-Threonine Kinases - metabolism
Receptor, ErbB-2 - metabolism
Receptors, Notch - metabolism
Signal Transduction - drug effects
Thiadiazoles - pharmacology
TOR Serine-Threonine Kinases
Tumors
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Summary:ERBB2/neu and Notch signaling are known to be deregulated in many human cancers. However, pathway cross-talk and dependencies are not well understood. In this study, we use an ERBB2-transgenic mouse model of breast cancer (neuT) to show that Notch signaling plays a critical role in tumor maintenance. Inhibition of the Notch pathway with a gamma-secretase inhibitor (GSI) decreased both the Notch and the mammalian target of rapamycin/AKT pathways. Antitumor activity resulting from GSI treatment was associated with decreased cell proliferation as measured by Ki67 and decreased expression of glucose transporter Glut1. Positron emission tomography (PET) imaging showed that the functional consequences of decreased Glut1 translated to reduced glucose uptake and correlated with antitumor effects as measured by micro-computed tomography imaging. The decrease of Glut1 in neuT tumors was also observed in several human breast cancer cell lines following GSI treatment. We provide evidence that approximately 27% of ERBB2-positive human breast cancer specimens display high expression of HES1, phospho-S6RP, and GLUT1. Together, these results suggest that pathways downstream of Notch signaling are, at least in part, responsible for promoting tumor growth in neuT and also active in both neuT and a subset of human breast cancers. These findings suggest that GSI may provide therapeutic benefit to a subset of ERBB2-positive breast cancers and that [(18)F]FDG-PET imaging may be useful in monitoring clinical response.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-09-3114