Pietilä Mika, Vijay Geraldine V, Soundararajan Rama, Yu Xian, Symmans William F, Sphyris Nathalie, Mani Sendurai A
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
Metastasis Research Centre, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
Sci Rep. 2016 Apr 11;6:23070. doi: 10.1038/srep23070.
Cancer cells with stem cell properties (CSCs) underpin the chemotherapy resistance and high therapeutic failure of triple-negative breast cancers (TNBCs). Even though CSCs are known to proliferate more slowly, they are sensitive to inhibitors of G2/M kinases such as polo-like kinase 1 (PLK1). Understanding the cell cycle regulatory mechanisms of CSCs will help target these cells more efficiently. Herein, we identify a novel role for the transcription factor FOXC2, which is mostly expressed in CSCs, in the regulation of cell cycle of CSC-enriched breast cancer cells. We demonstrate that FOXC2 expression is regulated in a cell cycle-dependent manner, with FOXC2 protein levels accumulating in G2, and rapidly decreasing during mitosis. Knockdown of FOXC2 in CSC-enriched TNBC cells delays mitotic entry without significantly affecting the overall proliferation rate of these cells. Moreover, PLK1 activity is important for FOXC2 protein stability, since PLK1 inhibition reduces FOXC2 protein levels. Indeed, FOXC2 expressing CSC-enriched TNBC cells are sensitive to PLK1 inhibition. Collectively, our findings demonstrate a novel role for FOXC2 as a regulator of the G2/M transition and elucidate the reason for the observed sensitivity of CSC-enriched breast cancer cells to PLK1 inhibitor.
具有干细胞特性的癌细胞（CSCs）是三阴性乳腺癌（TNBCs）化疗耐药和高治疗失败率的基础。尽管已知CSCs增殖较慢，但它们对G2/M激酶抑制剂如polo样激酶1（PLK1）敏感。了解CSCs的细胞周期调控机制将有助于更有效地靶向这些细胞。在此，我们确定了转录因子FOXC2在富含CSC的乳腺癌细胞周期调控中的新作用，FOXC2主要在CSCs中表达。我们证明FOXC2的表达以细胞周期依赖性方式受到调控，FOXC2蛋白水平在G2期积累，并在有丝分裂期间迅速下降。在富含CSC的TNBC细胞中敲低FOXC2会延迟有丝分裂进入，而不会显著影响这些细胞的总体增殖率。此外，PLK1活性对FOXC2蛋白稳定性很重要，因为抑制PLK1会降低FOXC2蛋白水平。事实上，表达FOXC2的富含CSC的TNBC细胞对PLK1抑制敏感。总之，我们的研究结果证明了FOXC2作为G2/M转换调节因子的新作用，并阐明了富含CSC的乳腺癌细胞对PLK1抑制剂敏感的原因。
