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Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function |
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Authors | ![]() | |
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 | Animals — Breast Neoplasms/drug therapy/genetics/pathology — Cell Cycle Proteins/physiology — Cell Proliferation — Genomic Instability — Humans — MCF-7 Cells — Mad2 Proteins/physiology — Mice — Microtubule-Associated Proteins/physiology — Nuclear Proteins/physiology — Phosphatidylinositol 3-Kinases/physiology — Spindle Apparatus/physiology — Taxoids/therapeutic use | |
Identifiers | PMID: 29017056 | |
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Research group | Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) (922) | |
Citation (ISO format) | 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 |