Sokolosky Melissa L, Stadelman Kristin M, Chappell William H, Abrams Stephen L, Martelli Alberto M, Stivala Franca, Libra Massimo, Nicoletti Ferdinando, Drobot Lyudmyla B, Franklin Richard A, Steelman Linda S, McCubrey James A
Department of Microbiology and Immunology Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
Oncotarget. 2011 Jul;2(7):538-50. doi: 10.18632/oncotarget.302.
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.
阐明乳腺癌细胞对化疗药物和激素药物的反应显然很重要，因为这些是常用的治疗方法。Ras/PI3K/PTEN/Akt/mTOR级联反应是一条常与化疗和激素耐药相关的信号通路。在本报告中的研究里，我们检测了组成型激活的Akt对MCF-7乳腺癌细胞对化疗药物、激素药物以及mTOR抑制剂敏感性的影响。表达组成型激活的Akt-1基因[∆Akt-1(CA)]的MCF-7细胞比缺乏∆Akt-1(CA)的细胞对阿霉素、依托泊苷和4-羟基他莫昔芬（4HT）更具抗性。表达∆Akt-1(CA)的细胞对mTOR抑制剂雷帕霉素高度敏感。此外，雷帕霉素降低了表达∆Akt-1(CA)的细胞中阿霉素、依托泊苷和4HT的半数抑制浓度（IC50），证明了一种治疗某些PI3K/PTEN/Akt/mTOR信号失调的乳腺癌的潜在改进方法。了解乳腺癌如何对化疗和激素疗法产生反应以及它们产生耐药性的机制，可能会提高我们治疗乳腺癌的能力。这些结果还证明了了解某些癌症中存在的突变的潜在重要性，这可能会带来更有效的治疗方法。
