title: Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model.
abstract: 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.
authors.affiliation: Department of Oncology, Pharmacology, Laboratory of Animal Research, Merck Research Laboratories, Boston, Massachusetts 02115, USA.
authors.forename: Clay L
authors.initials: CL
authors.lastname: Efferson
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Winkelmann
authors.forename: Christopher
authors.initials: C
authors.lastname: Ware
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.forename: Saverio
authors.initials: S
authors.lastname: Giampaoli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tammam
authors.forename: Shailendra
authors.initials: S
authors.lastname: Patel
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mesiti
authors.forename: John F
authors.initials: JF
authors.lastname: Reilly
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Gibson
authors.forename: Carolyn
authors.initials: C
authors.lastname: Buser
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Christopher
authors.initials: C
authors.lastname: Winter
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Clark
authors.forename: Giulio F
authors.initials: GF
authors.lastname: Draetta
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strack
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D003499:Cyclic S-Oxides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005947:Glucose / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D053829:Amyloid Precursor Protein Secretases; D003499:Cyclic S-Oxides; D019788:Fluorodeoxyglucose F18; D005947:Glucose; D051272:Glucose Transporter Type 1; D047908:Intracellular Signaling Peptides and Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D013830:Thiadiazoles; C523799:MRK 003; C495677:SLC2A1 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse