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. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2α that affects mitotic spindle formation. Reduced levels of PI3K-C2α reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2α also increases sensitivity of tumors to taxanes.

Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function / F. Gulluni, M. Martini, M.C. De Santis, C.C. Campa, A. Ghigo, J.P. Margaria, E. Ciraolo, I. Franco, U. Ala, L. Annaratone, D. Disalvatore, G. Bertalot, G. Viale, A. Noatynska, M. Compagno, S. Sigismund, F. Montemurro, M. Thelen, F. Fan, P. Meraldi, C. Marchiã², S. Pece, A. Sapino, R. Chiarle, P.P. Di Fiore, E. Hirsch. - In: CANCER CELL. - ISSN 1535-6108. - 32:4(2017 Oct 09), pp. 444-459.e7. [10.1016/j.ccell.2017.09.002]

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

G. Viale;Sigismund, Sara;S. Pece;P.P. Di Fiore;
2017-10-09

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. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2α that affects mitotic spindle formation. Reduced levels of PI3K-C2α reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2α also increases sensitivity of tumors to taxanes.
breast cancer; class II PI3K; clathrin; genomic stability; inter-microtubule bridge complex; mitosis; paclitaxel; spindle assembly checkpoint; tacc3; animals; breast neoplasms; cell cycle proteins; cell proliferation; humans; mcf-7 cells; mad2 proteins; mice; microtubule-associated proteins; nuclear proteins; phosphatidylinositol 3-kinases; spindle apparatus; taxoids; genomic instability; oncology; cell biology; cancer research
Settore MED/04 - Patologia Generale
Settore MED/08 - Anatomia Patologica
Settore BIO/13 - Biologia Applicata
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/531304
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