title: Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells.
abstract: Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs and radiation is clearly important as these are common treatment approaches. Signaling cascades often involved in chemo-, hormonal- and radiation resistance are the Ras/PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK and p53 pathways. In the following studies we have examined the effects of activation of the Ras/PI3K/PTEN/Akt/mTOR cascade in the response of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs and radiation. Activation of Akt by introduction of conditionally-activated Akt-1 gene could result in resistance to chemotherapeutic and hormonal based drugs as well as radiation. We have determined that chemotherapeutic drugs such as doxorubicin or the hormone based drug tamoxifen, both used to treat breast cancer, resulted in the activation of the Raf/MEK/ERK pathway which is often associated with a pro-proliferative, anti-apoptotic response. In drug sensitive MCF-7 cells which have wild-type p53; ERK, p53 and downstream p21 (Cip-1 ) were induced upon exposure to doxorubicin. In contrast, in the drug resistant cells which expressed activated Akt-1, much lower levels of p53 and p21 (Cip1) were induced upon exposure to doxorubicin. These results indicate the involvement of the Ras/PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK and p53 pathways in the response to chemotherapeutic and hormonal based drugs. Understanding how breast cancers respond to chemo- and hormonal-based therapies and radiation may enhance the ability to treat breast cancer more effectively.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: Patrick
authors.initials: P
authors.lastname: Navolanic
authors.forename: William H
authors.initials: WH
authors.lastname: Chappell
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.forename: Ellis W T
authors.initials: EW
authors.lastname: Wong
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Lyudmyla B
authors.initials: LB
authors.lastname: Drobot
authors.forename: Richard A
authors.initials: RA
authors.lastname: Franklin
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D004317:Doxorubicin; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus