Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function

作者：Gulluni, Federico; Martini, Miriam^*; De Santis, Maria Chiara; Campa, Carlo Cosimo; Ghigo, Alessandra; Margaria, Jean Piero; Ciraolo, Elisa; Franco, Irene; Ala, Ugo; Annaratone, Laura; Disalvatore, Davide; Bertalot, Giovanni; Viale, Giuseppe; Noatynska, Anna; Compagno, Mara; Sigismund, Sara; Montemurro, Filippo; Thelen, Marcus; Fan, Fan; Meraldi, Patrick; Marchio, Caterina; Pece, Salvatore; Sapino, Anna; Chiarle, Roberto; Di Fiore, Pier Paolo; Hirsch, Emilio^*

来源：Cancer Cell, 2017, 32(4): 444-+.

DOI：10.1016/j.ccell.2017.09.002

• INTERNATIONAL EXPERT CONSENSUS
• PRIMARY THERAPY
• KINETOCHORE FIBERS
• AURORA B
• CHECKPOINT
• CLATHRIN
• COMPLEX
• PI3K
• TACC3-CH-TOG-CLATHRIN
• PHOSPHORYLATION

Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase alpha (PI3K-C2 alpha) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2 alpha causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2 alpha expression is required for genomic stability. Reduced abundance of PI3K-C2 alpha in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2 alpha increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.

• 出版日期2017-10-9
• 单位西安交通大学