Abstract

EXCEED THE SPACE PROVIDED. Breastcanceris among the most commonformsof cancerwithover 180,000 newcases diagnosed inthe USA each year. Approximatelyhalf of all breastcancerpatientsdie from the diseasebecause metastaticbreastcancer remainsa generallyincurableandfatal disease.Cytotoxicdrugtreatment is an importantweapon againstcancer.However, cancerouscellsfrequentlydevelopdrug resistanceto these agents.We have determinedthat activationof the Ras/Raf/MEWERK signal transductioncascadewill lead to an increasedabilityof MCF-7 breastcancercellsto proliferatein the presenceof the chemotherapeuticdrugsdoxorubicinand paclitaxel.Consequencesof Raf activationmay includeincreasedexpressionof the drugtransportermdr-1, the anti-apoptoticbcl-2 gene, and autocrinegrowthfactorssuchas suchas amphiregulinwhichbindthe HER2 growth factor receptorimplicatedin the etiologyof breastcancer.In the proposedstudies,we will determinewhether inductionof mdr-1, bcl-2and autocrinegrowthfactor expressionbythe Ras/Raf/MEWERK signaltransductionpathwayis essentialfor inductionof breastcancerdrug resistanceandthe mechanismsby whichthisoccurs.To achievetheseobjectives,threespecific aims have been proposed:
Aim 1. To determinemechanismsby whichthe Ras/Raf/MEWERK pathwayregulatesmdr-1, bcl-2, and autocrinegrowthfactors andwhethertheirinducedexpression is requiredfor breastcancerdrugresistance,Aim 2. To determinemechanismsby whichthe Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathwaysinteractand regulatemdr-1, bcl-2and breastcancerdrugresistance.
Aim 3. To determinemechanismsbywhich Ras/Raf/MEWERK pathwayinfluencesthe redoxstatusof breastcancercellsto modulatetheirsensitivityto chemotherapeuticdrugs.Throughthese studies,moreinformationwillbe availableto treatbreast andothercancerpatientswithcombinationsof drugs,whichinhibitsignaltransductionand anti-apoptoticpathwaysleadingtodrug resistance. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098195-03
Application #
6835629
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$310,388
Indirect Cost

  Institution

Name
East Carolina University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858

  Publications

Taylor, Jackson R; Lehmann, Brian D; Chappell, William H et al. (2011) Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget 2:610-26
Steelman, Linda S; Navolanic, Patrick; Chappell, William H et al. (2011) Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle 10:3003-15
Sokolosky, Melissa L; Stadelman, Kristin M; Chappell, William H et al. (2011) Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget 2:538-50
McCubrey, James A; Abrams, Stephen L; Stadelman, Kristin et al. (2010) Targeting signal transduction pathways to eliminate chemotherapeutic drug resistance and cancer stem cells. Adv Enzyme Regul 50:285-307
Abrams, Stephen L; Steelman, Linda S; Shelton, John G et al. (2010) Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy. Cell Cycle 9:1839-46
Steelman, Linda S; Abrams, Stephen L; Shelton, John G et al. (2010) Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 9:1629-38
Abrams, Stephen L; Steelman, Linda S; Shelton, John G et al. (2010) The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9:1781-91
Martelli, Alberto M; Evangelisti, Camilla; Chiarini, Francesca et al. (2010) The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 1:89-103
Misaghian, N; Ligresti, G; Steelman, L S et al. (2009) Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 23:25-42
Chiarini, Francesca; Fala, Federica; Tazzari, Pier Luigi et al. (2009) Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 69:3520-8

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