PO-466 PI3K-C2A regulates mitotic spindle assembly and chemotherapy response in breast cancer

Abstract

IntroductionProper organisation of the mitotic spindle is key to genetic stability but the molecular components of inter-microtubule (MT) bridges that crosslink kinetochore fibres (K-fibres) are still largely unknown. Here, we identify class II phosphoinositide 3-OH kinase a (PI3K-C2α) as a limiting scaffold protein organising the clathrin and TACC3 complex crosslinking K-fibres.Material and methodsPik3c2a+/- mice were intercrossed with a transgenic strain expressing the activated HER-2/Neu oncogene in the mammary gland. Mice were weekly followed for survival, tumour appearance and growth. Primary Murine Mammary Epithelial Tumour (MMET) cells were derived from early and late stage tumours. Truncating PI3KC2α mutants were generated and interaction with TACC3 was tested. Levels of PI3K-C2α expression were assessed by IHC in breast cancer tissue microarrays (TMA) and correlated with response to chemotherapy.Results and discussionsLoss of PI3K-C2α expression is a frequent occurrence in breast cancer patients (48%) and correlates with local recurrence and metastatic disease. The heterozygous loss of PI3K-C2α initially delays tumour onset but, on the long run, leads to the convergent evolution of aggressive clones with mitotic checkpoint defects. In line with this, downregulation of PI3K-C2α promotes spindle alterations and aneuploidy, indicating that PI3K-C2α expression is a key determinant of genomic stability. As a consequence of the altered spindle, reduction of PI3K-C2α expression increases the sensitivity to anti-MT drugs, such as paclitaxel, in pre-clinical models and in breast cancer patients.ConclusionLoss of PI3K-C2α expression is a frequent occurrence in breast cancer patients (48%) and correlates with local recurrence and metastatic disease. The heterozygous loss of PI3K-C2α initially delays tumour onset but, on the long run, leads to the convergent evolution of aggressive clones with mitotic checkpoint defects. In line with this, downregulation of PI3K-C2α promotes spindle alterations and aneuploidy, indicating that PI3K-C2α expression is a key determinant of genomic stability. As a consequence of the altered spindle, reduction of PI3K-C2α expression increases the sensitivity to anti-MT drugs, such as paclitaxel, in pre-clinical models and in breast cancer patients.