CEP 55 is a determinant of cell fate during perturbed mitosis in breast cancer

Abstract

The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti‐mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase‐dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2‐MYC axis. Blocking MEK1/2‐PLK1 signaling therefore reduced outgrowth of basal‐like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2‐PLK1 represents a potential therapeutic strategy for MYC‐CEP55‐dependent basal‐like, triple‐negative breast cancers.

Cep55 overexpression promotes genomic instability and tumorigenesis in mice

“…Surprisingly, along with the bi- and multinucleated Cep55 Tg/Tg cells, the mononucleated cells also spent more time in mitosis, indicating that Cep55 overexpression prolonged mitotic duration independently of DNA content (Fig 5D). Moreover, consistent with our previous report in breast cancer 18 , Cep55 overexpression significantly impacted the duration of time to- and time spent in mitosis upon nocodazole treatment (Fig 5E-F). In particular, the Cep55 Tg/Tg cells largely prematurely exited mitosis during nocodazole arrest but the Cep55 wt/wt cells predominately died in mitosis (Fig 5G-J).…”

“…CEP55 has been shown to upregulate AKT phosphorylation through direct interaction with p110 catalytic subunit of PI3 kinase (PI3K) and enhance cell proliferation in vitro 14, 15, 17 . Likewise, we have shown that MYC regulates CEP55 transcriptionally in breast cancer 18 . Thus, to characterize the molecular signalling involved in cell proliferation and survival, we investigated the impact of Cep55 overexpression on Pi3k/Akt - and Erk-dependent signalling networks.…”

“…We have recently shown that Cep55 overexpression causes male-specific sterility by suppressing Foxo1 nuclear retention through the PI3K/AKT pathway in mice 17 . Furthermore, we showed that CEP55 is a determinant of aneuploid cell fate during perturbed mitosis in breast cancers and could be targeted through MEK1/2-PLK1 inhibition 18 . Moreover, Cep55 regulates spindle organisation and cell cycle progression in meiotic oocytes 19 .…”

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

“…All human BC lines and near‐normal mammary epithelial lines (MCF10A) were obtained from the American Type Culture Collection (ATCC) and maintained as described previously . Murine 4T1.2 cell line was obtained from Prof Robin Anderson (Olivia‐Newton john Cancer Research Institute, Australia).…”

“…All human BC lines and near-normal mammary epithelial lines (MCF10A) were obtained from the American Type Culture Collection (ATCC) and maintained as described previously. 19 Murine 4T1.2 cell line was obtained from Prof Robin Anderson (Olivia-Newton john Cancer Research Institute, Australia). D492 mammary epithelial cell line was provided by Dr Thorarinn Gudjonsson (The Panum Institute, Copenhagen, Denmark) and were maintained as described previously.…”