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    Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells

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    Author
    Taylor, Jackson R.; Lehmann, Brian D.; Chappell, William H.; Abrams, Stephen L.; Steelman, Linda S.; McCubrey, McCubrey
    Abstract
    Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.
    URI
    http://hdl.handle.net/10342/7935
    Subject
    Akt, ERK, mTOR, Senescence, Drug Resistance, Tamoxifen
    Date
    2011-08-30
    Citation:
    APA:
    Taylor, Jackson R., & Lehmann, Brian D., & Chappell, William H., & Abrams, Stephen L., & Steelman, Linda S., & McCubrey, McCubrey. (August 2011). Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget, (2:8), p.610–626. Retrieved from http://hdl.handle.net/10342/7935

    Display/Hide MLA, Chicago and APA citation formats.

    MLA:
    Taylor, Jackson R., and Lehmann, Brian D., and Chappell, William H., and Abrams, Stephen L., and Steelman, Linda S., and McCubrey, McCubrey. "Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells". Oncotarget. 2:8. (610–626.), August 2011. May 19, 2022. http://hdl.handle.net/10342/7935.
    Chicago:
    Taylor, Jackson R. and Lehmann, Brian D. and Chappell, William H. and Abrams, Stephen L. and Steelman, Linda S. and McCubrey, McCubrey, "Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells," Oncotarget 2, no. 8 (August 2011), http://hdl.handle.net/10342/7935 (accessed May 19, 2022).
    AMA:
    Taylor, Jackson R., Lehmann, Brian D., Chappell, William H., Abrams, Stephen L., Steelman, Linda S., McCubrey, McCubrey. Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget. August 2011; 2(8) 610–626. http://hdl.handle.net/10342/7935. Accessed May 19, 2022.
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