Abstract
Background: Notch is a cell signaling pathway that is highly conserved in all metazoans and is the master responsible for cell differentiation and cross communication with other signaling pathways such as Wingless and Hedgehog. In most cancers, the Notch signaling pathway is altered, causing normal controls of vital processes such as cell cycle, differentiation and apoptosis to be compromised, leading the cell to a carcinogenic state. However, the inherent nature of the Notch signaling pathway of regulating the activation or repression of other signaling pathways related to differentiation and cell cycle has caused the strategies against breast cancer to be even more specialized and to know more efficiently the suitable method againts the disease.
Methods: Different bibliographies and articles related to the Notch pathway and the biology of cancer were reviewed, especially with breast cancer, as well as the participation of other signaling pathways directly and indirectly related to the constitutive activation of the Notch pathway and relating the threads loose to create a general conceptual map of the wide effects of the malfunction of the Notch pathway in this disease so that we can understand from another point of view how this flow of information can be controlled.
Results: The study of Notch signaling during more than a decade has gave us new clues to elucidate the mechanisms of their finely orchestrated molecular functioning and how this signaling path interacts with another signaling pathways in differentiation, survival, cell cycle and apoptosis. Notch Signaling is a professional in the process of differentiation and cross-talk communication with another signaling pathways, especially with the WNT and Hh pathways. The responsibility of WNT pathway is to maintain the survival and growth controls, having direct effects on the cell cycle and the Hh pathway is to maintain a state of diferentiation trought the life of the cell and the cell migration instead, cell cycle and the response to growth stimuli of angiogenesis, exacerbated characteristics of many breast cancer.
Conclusion: This review highlights the complex communication network between the WNT, Hh and Notch Signaling and the therapies in the field of cancer that are not entirely effective, however, most of the therapies that are currently being developed are including the Notch Signaling as a target quite promising and is for its regulatory effect with other signaling pathways.
Keywords: Notch-signaling pathway, carcinogenesis, signal transduction, breast cancer, CSL, ligand-receptor binding (GSIs).
Graphical Abstract
[http://dx.doi.org/10.1016/j.ydbio.2009.09.030] [PMID: 19782677]
[http://dx.doi.org/10.1016/S1084-9521(02)00179-9] [PMID: 12651094]
[http://dx.doi.org/10.1186/1471-213X-8-11] [PMID: 18237417]
[PMID: 9169839]
[http://dx.doi.org/10.1074/jbc.M404589200] [PMID: 15123610]
[http://dx.doi.org/10.1016/S0092-8674(00)00198-7] [PMID: 11136980]
[http://dx.doi.org/10.1038/nature02190] [PMID: 14712268]
[http://dx.doi.org/10.1126/science.284.5415.770] [PMID: 10221902]
[http://dx.doi.org/10.1006/dbio.2000.9960] [PMID: 11112321]
[http://dx.doi.org/10.1016/j.ijbiomac.2008.08.012] [PMID: 18809430]
[http://dx.doi.org/10.1006/dbio.2000.9923] [PMID: 11071771]
[http://dx.doi.org/10.1038/35019000] [PMID: 10935626]
[PMID: 10504334]
[http://dx.doi.org/10.1074/jbc.274.37.25986] [PMID: 10473542]
[http://dx.doi.org/10.1016/S0092-8674(02)01114-5] [PMID: 12526814]
[http://dx.doi.org/10.1186/s13008-016-0025-2] [PMID: 27708688]
[http://dx.doi.org/10.1016/S0092-8674(02)00875-9] [PMID: 12230979]
[http://dx.doi.org/10.1016/0092-8674(94)90070-1] [PMID: 8001118]
[http://dx.doi.org/10.1093/emboj/cdf549] [PMID: 12374742]
[http://dx.doi.org/10.1128/MCB.25.23.10379-10390.2005] [PMID: 16287852]
[http://dx.doi.org/10.1128/MCB.21.17.6080-6089.2001] [PMID: 11486045]
[http://dx.doi.org/10.1016/0092-8674(94)90159-7] [PMID: 8181063]
[http://dx.doi.org/10.1006/bbrc.2000.3354] [PMID: 10964718]
[PMID: 9916679]
[PMID: 9916679]
[PMID: 14695182]
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0677] [PMID: 20971825]
[http://dx.doi.org/10.1038/sj.onc.1201035] [PMID: 9150355]
[http://dx.doi.org/10.1101/gad.6.3.345] [PMID: 1372276]
[http://dx.doi.org/10.1128/JVI.66.4.2594-2599.1992] [PMID: 1312643]
[http://dx.doi.org/10.1038/377355a0] [PMID: 7566092]
[http://dx.doi.org/10.1016/0092-8674(91)90111-B] [PMID: 1831692]
[http://dx.doi.org/10.1101/gad.276304] [PMID: 14701881]
[http://dx.doi.org/10.1016/0092-8674(85)90229-6] [PMID: 3935325]
[http://dx.doi.org/10.1073/pnas.1000896107] [PMID: 20194747]
[http://dx.doi.org/10.1046/j.1365-2613.1998.00068.x] [PMID: 9797716]
[PMID: 1928301]
[PMID: 2426509]
[http://dx.doi.org/10.1002/ijc.1985.36.3.299] [PMID: 2411673]
[http://dx.doi.org/10.1111/j.1432-0436.1998.00201.x] [PMID: 9745711]
[http://dx.doi.org/10.1186/bcr298] [PMID: 11434871]
[http://dx.doi.org/10.1074/jbc.M703601200] [PMID: 17664272]
[http://dx.doi.org/10.1074/jbc.274.11.7238] [PMID: 10066785]
[PMID: 9102301]
[PMID: 11861470]
[PMID: 10079231]
[http://dx.doi.org/10.1006/viro.2001.0867] [PMID: 11448155]
[http://dx.doi.org/10.1101/cshperspect.a008052] [PMID: 22438566]
[http://dx.doi.org/10.1038/labinvest.3700700] [PMID: 18059366]
[http://dx.doi.org/10.1084/jem.183.5.2025] [PMID: 8642313]
[http://dx.doi.org/10.1128/JVI.61.1.66-74.1987] [PMID: 3023708]
[http://dx.doi.org/10.3892/ijmm.14.5.779] [PMID: 15492845]
[http://dx.doi.org/10.2353/ajpath.2006.050416] [PMID: 16507912]
[http://dx.doi.org/10.1016/j.ccr.2014.02.018] [PMID: 24651013]
[PMID: 21193018]
[http://dx.doi.org/10.1242/dev.000786] [PMID: 17329370]
[http://dx.doi.org/10.1101/gad.6.12b.2620] [PMID: 1340473]
[http://dx.doi.org/10.1006/bbrc.1996.0959] [PMID: 8687460]
[http://dx.doi.org/10.1242/dev.02403] [PMID: 16728479]
[http://dx.doi.org/10.1128/MCB.25.10.4262-4271.2005] [PMID: 15870295]
[http://dx.doi.org/10.1128/MCB.20.16.6170-6183.2000] [PMID: 10913198]
[http://dx.doi.org/10.1038/sj.onc.1208139] [PMID: 15467735]
[http://dx.doi.org/10.1242/dev.01519] [PMID: 15539483]
[http://dx.doi.org/10.1093/emboj/20.16.4454] [PMID: 11500373]
[http://dx.doi.org/10.1073/pnas.0308319100] [PMID: 14745018]
[http://dx.doi.org/10.1677/JOE-08-0094] [PMID: 19039095]
[http://dx.doi.org/10.1200/JCO.2005.05.064] [PMID: 15961768]
[http://dx.doi.org/10.1128/MCB.20.23.8667-8675.2000] [PMID: 11073968]
[http://dx.doi.org/10.1101/gad.12.22.3488] [PMID: 9832502]
[PMID: 10473088]
[http://dx.doi.org/10.1210/me.2013-1196] [PMID: 24606123]
[http://dx.doi.org/10.1128/MCB.01539-06] [PMID: 17074804]
[http://dx.doi.org/10.1074/jbc.M313466200] [PMID: 15123687]
[http://dx.doi.org/10.1006/bbrc.1994.2887] [PMID: 7811275]
[http://dx.doi.org/10.1074/jbc.M405938200] [PMID: 15355984]
[http://dx.doi.org/10.1074/jbc.M203380200] [PMID: 12048199]
[http://dx.doi.org/10.1387/ijdb.041815jb] [PMID: 15349822]
[http://dx.doi.org/10.1101/gad.1424006] [PMID: 16751178]
[http://dx.doi.org/10.1042/BC20040094] [PMID: 15715524]
[http://dx.doi.org/10.1016/j.ceb.2007.02.007] [PMID: 17306971]
[http://dx.doi.org/10.1038/ncb1240] [PMID: 15778706]
[http://dx.doi.org/10.1016/j.ydbio.2006.02.043] [PMID: 16581056]
[http://dx.doi.org/10.1016/j.stem.2008.08.001] [PMID: 18940734]
[http://dx.doi.org/10.1007/s11010-014-2163-7] [PMID: 25073953]
[http://dx.doi.org/10.1038/sj.onc.1203719] [PMID: 10951584]
[http://dx.doi.org/10.1073/pnas.0603371103] [PMID: 16751266]
[http://dx.doi.org/10.1186/bcr2200] [PMID: 19025652]
[http://dx.doi.org/10.1016/j.stem.2008.05.018] [PMID: 18593563]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1069] [PMID: 16166334]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3054] [PMID: 16452208]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1720] [PMID: 17875709]
[http://dx.doi.org/10.1016/j.cell.2008.04.013] [PMID: 18455982]
[http://dx.doi.org/10.1111/bph.13211] [PMID: 26040571]
[http://dx.doi.org/10.1177/1066896911427035] [PMID: 22084425]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2846] [PMID: 20530699]
[http://dx.doi.org/10.1038/ncponc0794] [PMID: 17464337]
[PMID: 12183437]
[http://dx.doi.org/10.1128/MCB.00707-07] [PMID: 17893320]
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1942] [PMID: 16489083]
[http://dx.doi.org/10.4161/cbt.9.1.10392] [PMID: 19901561]
[http://dx.doi.org/10.1038/sj.onc.1207984] [PMID: 15286704]
[http://dx.doi.org/10.1093/nar/19.21.5943] [PMID: 1945881]
[http://dx.doi.org/10.1093/nar/gkg703] [PMID: 12930944]
[http://dx.doi.org/10.1016/j.ijrobp.2003.11.041] [PMID: 15142631]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-2017] [PMID: 18281472]
[http://dx.doi.org/10.1093/annonc/mdp492] [PMID: 19901010]
[http://dx.doi.org/10.1038/sj.onc.1206758] [PMID: 14528285]
[http://dx.doi.org/10.1200/JCO.2011.36.8282] [PMID: 22529266]
[http://dx.doi.org/10.1371/journal.pone.0046512] [PMID: 23056328]
[http://dx.doi.org/10.1038/nature08878] [PMID: 20393564]