Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development
Restricted accessResearch articleFirst published online January, 2017
Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development
Wap-Int3 transgenic females expressing the Notch4 intracellular domain (designated Int3) from the whey acidic protein promoter exhibit two phenotypes in the mammary gland: blockage of lobuloalveolar development and lactation, and tumor development with 100% penetrance. Previously, we have shown that treatment of Wap-Int3 tumor bearing mice with Imatinib mesylate (Gleevec) is associated with complete regression of the tumor. In the present study, we show that treatment of Wap-Int3 mice during day 1 through day 6 of pregnancy with Gleevec leads to the restoration of their lobuloalveolar development and ability to lactate in subsequent pregnancies in absence of Gleevec treatment. In addition, these mice do not develop mammary tumors. We investigated the mechanism for Gleevec regulation of Notch signaling and found that Gleevec treatment results in a loss of Int3 protein but not of Int3 mRNA in HC11 mouse mammary epithelial cells expressing Int3. The addition of MG-132, a proteasome inhibitor, shows increased ubiquitination of Int3 in the presence of Gleevec. Thus, Gleevec affects the stability of Int3 by promoting the degradation of Int3 via E3 ubiquitin ligases targeting it for the proteasome degradation. Gleevec is a tyrosine kinase inhibitor that acts on c-Kit and PDGFR. Therefore, we investigated the downstream substrate kinase GSK3β to ascertain the possible role that this kinase might play in the stability of Int3. Data show that Gleevec degradation of Int3 is GSK3β dependent. We have expanded our study of the effects Gleevec has on tumorigenesis of other oncogenes. We have found that anchorage-independent growth of HC11-c-Myc cells as well as tumor growth in nude mice is inhibited by Gleevec treatment. As with Int3, Gleevec treatment appears to destabilize the c-Myc protein but not mRNA. These results indicate that Gleevec could be a potential therapeutic drug for patients bearing Notch4 and/or c-Myc positive breast carcinomas.
CallahanREganSE. Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia2004; 9: 145–63.
3.
SmithGHGallahanDDiellaFJhappanCMerlinoGMerlinoGCallahanR. Constitutive expression of a truncated INT3 gene in mouse mammary epithelium impairs differentiation and functional development. Cell Growth Differ1995; 6: 563–77.
4.
JhappanCGallahanDStahleCChuESmithGHMerlinoGCallahanR. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev1992; 6: 345–55.
5.
GallahanDJhappanCRobinsonGHennighausenLSharpRKordonECallahanRMerlinoGSmithGH. Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis. Cancer Res1996; 56: 1775–85.
6.
BolosVMiraEMartinez-PovedaBLuxanGCanameroMMartínez-ACMañesSde la PompaJL. Notch activation stimulates migration of breast cancer cells and promotes tumor growth. Breast Cancer Res2013; 15: R54–R54.
7.
SimmonsMJSerraRHermanceNKelliherMA. NOTCH1 inhibition in vivo results in mammary tumor regression and reduced mammary tumorsphere-forming activity in vitro. Breast Cancer Res2012; 14: R126–R126.
8.
HuCDievartALupienMCalvoETremblayGJolicoeurP. Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol2006; 168: 973–90.
9.
RaafatABargoSAnverMRCallahanR. Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh). Oncogene2004; 23: 9401–07.
10.
BallRKFriisRRSchoenenbergerCADopplerWGronerB. Prolactin regulation of beta-casein gene expression and of a cytosolic 120-kd protein in a cloned mouse mammary epithelial cell line. EMBO J1988; 7: 2089–95.
11.
RobbinsJBlondelBJGallahanDCallahanR. Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells. J Virol1992; 66: 2594–99.
12.
RaafatALawsonSBargoSKlauzinskaMStrizziLBargoSKimuraKSalomonDCallahanR. Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene2009; 28: 219–30.
13.
RaafatAZoltan-JonesAStrizziLBargoSKimuraKSalomonDCallahanR. Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis. Oncogene2007; 26: 662–72.
14.
NetzerWJDouFCaiDVeachDJeanSLiYBornmannWGClarksonBXuHGreengardP. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci USA2003; 100: 12444–49.
15.
EiseleYSBaumannMKleblBNordhammerCJuckerMKilgerE. Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-beta degrading enzyme neprilysin. Mol Biol Cell2007; 18: 3591–600.
16.
PalermoRChecquoloSBellaviaDTaloraCScrepantiI. The molecular basis of notch signaling regulation: a complex simplicity. Curr Mol Med2014; 14: 34–44.
17.
EspinosaLIngles-EsteveJAguileraCBigasA. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem2003; 278: 32227–35.
18.
AnderssonERSandbergRLendahlU. Notch signaling: simplicity in design, versatility in function. Development2011; 138: 3593–612.
DobleBWWoodgettJR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci2003; 116: 1175–86.
21.
WuDPanW. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci2010; 35: 161–68.
22.
GrimesCAJopeRS. CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem2001; 78: 1219–32.
23.
ArcaroAGuerreiroAS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics2007; 8: 271–306.
24.
YasudaASawaiHTakahashiHOchiNMatsuoYFunahashiHSatoMOkadaYTakeyamaHManabeT. Stem cell factor/c-kit receptor signaling enhances the proliferation and invasion of colorectal cancer cells through the PI3K/Akt pathway. Dig Dis Sci2007; 52: 2292–300.
25.
MyungJKimKBCrewsCM. The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev2001; 21: 245–73.
26.
JohnsonDE. The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer2015; 22: T1–17.
27.
D’SouzaBMiyamotoAWeinmasterG. The many facets of Notch ligands. Oncogene2008; 27: 5148–67.
28.
Le BrasSLoyerNLe BorgneR. The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic2011; 12: 149–61.
29.
MorettiJBrouC. Ubiquitinations in the notch signaling pathway. Int J Mol Sci2013; 14: 6359–81.
30.
Gupta-RossiNLe BailOGonenHBrouCLogeatFSixECiechanoverAIsraëlA. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J Biol Chem2001; 276: 34371–78.
31.
ObergCLiJPauleyAWolfEGurneyMLendahlU. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J Biol Chem2001; 276: 35847–53.
32.
WuGLyapinaSDasILiJGurneyMPauleyAChuiIDeshaiesRJKitajewskiJ. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol2001; 21: 7403–15.
33.
RaafatAStrizziLLashinKGinsburgEMcCurdyDSalomonDSmithGHMedinaDCallahanR. Effects of age and parity on mammary gland lesions and progenitor cells in the FVB/N-RC mice. PLoS One2012; 7: e43624–e43624.
34.
KlauzinskaMMcCurdyDRangelMCVaidyanathACastroNPShenMMGonzalesMBertoletteDBiancoCCallahanRSalomonDSRaafatA. Cripto-1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor-mediated pathway. Am J Pathol2015; 185: 2907–22.
35.
KlauzinskaMBaljinnyamBRaafatARodriguez-CanalesJStrizziLGreerYERubinJSCallahanR. Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells. J Cell Physiol2012; 227: 1960–71.
36.
AndersonSNTowneDLBurnsDJWarriorU. A high-throughput soft agar assay for identification of anticancer compound. J Biomol Screen2007; 12: 938–45.
37.
RaafatAGoldharASKlauzinskaMXuKAmirjazilIMcCurdyDLashinKSalomonDVonderhaarBKEganSCallahanR. Expression of Notch receptors, ligands, and target genes during development of the mouse mammary gland. J Cell Physiol2011; 226: 1940–52.
38.
OakesSRHiltonHNOrmandyCJ. The alveolar switch: coordinating the proliferative cues and cell fate decisions that drive the formation of lobuloalveoli from ductal epithelium. Breast Cancer Res2006; 8: 207–207.
39.
RockKLGrammCRothsteinLClarkKSteinRDickLHwangDGoldbergAL. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell1994; 78: 761–71.
40.
WelckerMClurmanBE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer2008; 8: 83–93.
41.
FryerCJWhiteJBJonesKA. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell2004; 16: 509–20.
42.
MoJSKimMYHanSOKimISAnnEJLeeKSSeoMSKimJYLeeSCParkJWChoiEJSeongJYJoeCOFaesslerRParkHS. Integrin-linked kinase controls Notch1 signaling by down-regulation of protein stability through Fbw7 ubiquitin ligase. Mol Cell Biol2007; 27: 5565–74.
CoghlanMPCulbertAACrossDACorcoranSLYatesJWPearceNJRauschOLMurphyGJCarterPSRoxbee CoxLMillsDBrownMJHaighDWardRWSmithDGMurrayKJReithADHolderJC. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol2000; 7: 793–803.
45.
McCubreyJASteelmanLSBertrandFEDavisNMSokoloskyMAbramsSLMontaltoGD’AssoroABLibraMNicolettiFMaestroRBaseckeJRakusDGizakADemidenkoZNCoccoLMartelliAMCervelloM. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget2014; 5: 2881–911.
46.
AnderssonERLendahlU. Therapeutic modulation of Notch signalling – are we there yet?Nat Rev Drug Discov2014; 13: 357–78.
47.
ChangTHKunasegaranKTarulliGADe SilvaDVoorhoevePMPietersenAM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res2014; 16: R1–R1.
48.
JhappanCGeiserAGKordonECBagheriDHennighausenLRobertsABSmithGHMerlinoG. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J1993; 12: 1835–45.
49.
KordonECMcKnightRAJhappanCHennighausenLMerlinoGSmithGH. Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population. Dev Biol1995; 168: 47–61.
50.
BrunoRDBoulangerCASmithGH. Notch-induced mammary tumorigenesis does not involve the lobule-limited epithelial progenitor. Oncogene2012; 31: 60–7.
51.
SmithGHVonderhaarBK. Functional differentiation in mouse mammary gland epithelium is attained through DNA synthesis, inconsequent of mitosis. Dev Biol1981; 88: 167–79.
52.
VonderhaarBKSmithGHPauleyRJRosenJMTopperYJ. Difference between mammary epithelial cells from mature virgin and primiparous mice. Cancer Res1978; 38: 4059–65.
53.
Dos SantosCODolzhenkoEHodgesESmithADHannonGJ. An epigenetic memory of pregnancy in the mouse mammary gland. Cell Rep2015; 11: 1102–09.
54.
YamajiDNaRFeuermannYPechholdSChenWRobinsonGWHennighausenL. Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A. Genes Dev2009; 23: 2382–87.
55.
BoothBWBoulangerCASmithGH. Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation. J Cell Physiol2007; 3: 729–36.
56.
VisvaderJE. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev2009; 23: 2563–77.
57.
DontuGJacksonKWMcNicholasEKawamuraMJAbdallahWMWichaMS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res2004; 6: R605–15.
58.
BuonoKDRobinsonGWMartinCShiSStanleyPTanigakiKHonjoTHennighausenL. The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy. Dev Biol2006; 293: 565–80.
59.
MazzoneMSelforsLMAlbeckJOverholtzerMSaleSCarrollDLPandyaDLuYMillsGBAsterJCArtavanis-TsakonasSBruggeJS. Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci USA2010; 107: 5012–17.
60.
BriskenCO’MalleyB. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol2010; 2: a003178–a003178.
61.
FengYMankaDWagnerKUKhanSA. Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci USA2007; 104: 14718–23.
Kouros-MehrHSlorachEMSternlichtMDWerbZ. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell2006; 127: 1041–55.
64.
BriskenCKaurSChavarriaTEBinartNSutherlandRLWeinbergRAKellyPAOrmandyCJ. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol1999; 210: 96–106.
VisvaderJEStinglJ. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev2014; 28: 1143–58.
67.
RibeiroJRFreimanRN. Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer. J Steroid Biochem Mol Biol2014; 143: 160–73.
68.
ObrAEEdwardsDP. The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol Cell Endocrinol2012; 357: 4–17.
69.
FangTCYashiro-OhtaniYDel BiancoCKnoblockDMBlacklowSCPearWS. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity2007; 27: 100–10.
70.
BourasTPalBVaillantFHarburgGAsselin-LabatMLOakesSRLindemanGJVisvaderJE. Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell2008; 3: 429–41.
71.
OakesSRGallego-OrtegaDOrmandyCJ. The mammary cellular hierarchy and breast cancer. Cell Mol Life Sci2014; 71: 4301–24.
72.
CiechanoverA. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ2005; 12: 1178–90.
73.
LeckerSHGoldbergALMitchWE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol2006; 17: 1807–19.
74.
RechsteinerMRogersSW. PEST sequences and regulation by proteolysis. Trends Biochem Sci1996; 21: 267–71.
75.
LiuLEisenmanRN. Regulation of c-Myc protein abundance by a protein phosphatase 2A-glycogen synthase kinase 3beta-negative feedback pathway. Genes Cancer2012; 3: 23–36.
76.
GregoryMAQiYHannSR. Phosphorylation by glycogen synthase kinase-3 controls c-Myc proteolysis and subnuclear localization. J Biol Chem2003; 278: 51606–12.
77.
VervoortsJLuscher-FirzlaffJLuscherB. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem2006; 281: 34725–29.
78.
GregoryMAHannSR. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol2000; 20: 2423–35.
79.
SpeiserJJErsahinCOsipoC. The functional role of Notch signaling in triple-negative breast cancer. Vitam Horm2013; 93: 277–306.
80.
Al-HussainiHSubramanyamDReedijkMSridharSS. Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther2011; 10: 9–15.
