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

Gulluni, Federico
Martini, Miriam
De Santis, Maria Chiara
Campa, Carlo Cosimo
Ghigo, Alessandra
Margaria, Jean Piero
Ciraolo, Elisa
Franco, Irene
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Published in Cancer Cell. 2017, vol. 32, no. 4, p. 444-459.e7
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.
Keywords AnimalsBreast Neoplasms/drug therapy/genetics/pathologyCell Cycle Proteins/physiologyCell ProliferationGenomic InstabilityHumansMCF-7 CellsMad2 Proteins/physiologyMiceMicrotubule-Associated Proteins/physiologyNuclear Proteins/physiologyPhosphatidylinositol 3-Kinases/physiologySpindle Apparatus/physiologyTaxoids/therapeutic use
PMID: 29017056
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Research group Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) (922)
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GULLUNI, Federico et al. Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. In: Cancer Cell, 2017, vol. 32, n° 4, p. 444-459.e7. doi: 10.1016/j.ccell.2017.09.002 https://archive-ouverte.unige.ch/unige:107106

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Deposited on : 2018-08-16

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