Centrosome Clustering Is a Tumor-selective Target for the Improvement of Radiotherapy in Breast Cancer Cells

Abstract

Owing to the frequent observation of centrosome amplification in human cancers, cancer cells have a unique mechanism to suppress detrimental multipolar division by clustering multiple centrosomes into two functional spindle poles, known as centrosome clustering. This study investigated whether inhibition of centrosome clustering enhances the radiation sensitivity of breast cancer cells. In this study, inhibition of centrosome clustering was examined by using various centrosome-declustering agents and KIFC1 siRNA in three breast cancer cell lines and two normal fibroblast cell lines. The combination effect of radiation and centrosome declustering was evaluated by cell viability, clonogenic, immunofluorescence assay. This study showed that targeting centrosome clustering enhanced the efficacy of radiotherapy of breast cancer cells with less damage to normal cells. Ionizing radiation induced centrosome amplification in breast cancer cells, but not in normal fibroblast cells. Notably, we showed that centrosome declustering efficiently radiosensitized the centrosome-amplified breast cancer cells through induction of multipolar spindles but did not affect the viability of normal fibroblasts in response to irradiation. Furthermore, KIFC1 mediated the radiosensitivity of the centrosome-amplified breast cancer cells. Our data provided the first evidence that centrosome clustering is a tumor-selective target for the improvement of radiotherapy in breast cancer cells.