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

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Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-10-09 , DOI: 10.1016/j.ccell.2017.09.002
Federico Gulluni ₁ , Miriam Martini ₁ , Maria Chiara De Santis ₁ , Carlo Cosimo Campa ₁ , Alessandra Ghigo ₁ , Jean Piero Margaria ₁ , Elisa Ciraolo ₁ , Irene Franco ₁ , Ugo Ala ₁ , Laura Annaratone ₂ , Davide Disalvatore ₃ , Giovanni Bertalot ₄ , Giuseppe Viale ₅ , Anna Noatynska ₆ , Mara Compagno ₇ , Sara Sigismund ₃ , Filippo Montemurro ₈ , Marcus Thelen ₉ , Fan Fan ₁₀ , Patrick Meraldi ₆ , Caterina Marchiò ₂ , Salvatore Pece ₁₁ , Anna Sapino ₁₂ , Roberto Chiarle ₇ , Pier Paolo Di Fiore ₁₃ , Emilio Hirsch ₁

Affiliation

Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy.
Department of Medical Sciences, University of Torino, Turin, Italy; Pathology Unit, Department of Laboratory Medicine, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy.
Division of Pathology, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Unit of Investigative Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy.
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Department of Biological Science and Bioengineering, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China.
Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.
Department of Medical Sciences, University of Torino, Turin, Italy; Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy.
IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy; Program of Molecular Medicine, IEO, European Institute of Oncology, Milan, Italy; Department of Oncology and Hemato-oncology (DIPO), University of Milan, Milan, Italy.

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.

中文翻译：

乳腺癌中的有丝分裂纺锤体组装和基因组稳定性需要 PI3K-C2α 支架功能。

有丝分裂纺锤体的正确组织是遗传稳定性的关键，但交联动粒纤维（K-纤维）的微管间桥的分子成分在很大程度上仍是未知的。在这里，我们确定了 II 类磷酸肌醇 3-OH 激酶 α (PI3K-C2α) 的激酶独立功能，作为限制支架蛋白组织网格蛋白和 TACC3 复合物交联 K 纤维。PI3K-C2α 的下调导致纺锤体改变、后期开始延迟和非整倍体，表明 PI3K-C2α 表达是基因组稳定性所必需的。乳腺癌模型中 PI3K-C2α 丰度的降低最初会损害肿瘤的生长，但随后会导致具有有丝分裂检查点缺陷的快速生长克隆的趋同进化。由于主轴改变，

更新日期：2017-10-09

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