title: Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy.
abstract: Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [∆Akt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking ∆Akt-1(CA). Cells which expressed ∆Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed ∆Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies.
authors: Department of Microbiology and Immunology Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Melissa L
authors: ML
authors: Sokolosky
authors: Kristin M
authors: KM
authors: Stadelman
authors: William H
authors: WH
authors: Chappell
authors: Stephen L
authors: SL
authors: Abrams
authors: Alberto M
authors: AM
authors: Martelli
authors: Franca
authors: F
authors: Stivala
authors: Massimo
authors: M
authors: Libra
authors: Ferdinando
authors: F
authors: Nicoletti
authors: Lyudmyla B
authors: LB
authors: Drobot
authors: Richard A
authors: RA
authors: Franklin
authors: Linda S
authors: LS
authors: Steelman
authors: James A
authors: JA
authors: McCubrey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen; D005047:Etoposide; D004317:Doxorubicin; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus