title: Targeting Akt3 signaling in triple-negative breast cancer.
abstract: 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.
authors: Authors' Affiliations: Department of Pathology, Beth Israel Deaconess Medical Center; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Y Rebecca
authors: YR
authors: Chin
authors: Taku
authors: T
authors: Yoshida
authors: Andriy
authors: A
authors: Marusyk
authors: Andrew H
authors: AH
authors: Beck
authors: Kornelia
authors: K
authors: Polyak
authors: Alex
authors: A
authors: Toker
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059368:RNA Isoforms; D015398:Signal Transduction; D018874:Spheroids, Cellular; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D059368:RNA Isoforms; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt