期刊
CANCER RESEARCH
卷 74, 期 3, 页码 964-973出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2175
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资金
- NIH [K99CA157945, CA092644, T32 CA081156-09]
- Susan G. Komen Foundation
- ImClone/Eli Lilly
- Klarman Family Foundation
Triple-negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, in general has a poor outcome. To identify new therapeutic targets in TNBC, we performed a short hairpin RNA (shRNA) screen for protein kinases commonly amplified and overexpressed in breast cancer. Using this approach, we identified AKT3 as a gene preferentially required for the growth of TNBCs. Downregulation of Akt3 significantly inhibits the growth of TNBC lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, whereas loss of Akt1 or Akt2 have more modest effects. Akt3 silencing markedly upregulates the p27 cell-cycle inhibitor and this is critical for the ability of Akt3 to inhibit spheroid growth. In contrast with Akt1, Akt3 silencing results in only a minor enhancement of migration and does not promote invasion. Depletion of Akt3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. These results imply that Akt3 has a specific function in TNBCs; thus, its therapeutic targeting may provide a new treatment option for this tumor subtype. (C) 2013 AACR.
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