| Literature DB >> 29017056 |
Federico Gulluni1, Miriam Martini2, Maria Chiara De Santis1, Carlo Cosimo Campa1, Alessandra Ghigo1, Jean Piero Margaria1, Elisa Ciraolo1, Irene Franco1, Ugo Ala1, Laura Annaratone3, Davide Disalvatore4, Giovanni Bertalot5, Giuseppe Viale6, Anna Noatynska7, Mara Compagno8, Sara Sigismund4, Filippo Montemurro9, Marcus Thelen10, Fan Fan11, Patrick Meraldi7, Caterina Marchiò3, Salvatore Pece12, Anna Sapino13, Roberto Chiarle8, Pier Paolo Di Fiore14, Emilio Hirsch15.
Abstract
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 α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability. Reduced abundance of PI3K-C2α 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-C2α increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.Entities:
Keywords: Class II PI3K; TACC3; breast cancer; clathrin; genomic stability; inter-microtubule bridge complex; mitosis; paclitaxel; spindle assembly checkpoint
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Year: 2017 PMID： 29017056 DOI： 10.1016/j.ccell.2017.09.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743