Checkpoint Pathways Activated by Re-Replication in Breast Cancer Cells

摘要

Emi-1 has been known as an inhibitor of APC (anaphase promoting complex). The depletion of Emi-1 would prematurely activate APC, lead to simultaneous degradation of geminin and cyclin A, and induce re-replication at least in colon cancer cell lines and breast epithelial cell MCF10A. We proposed Emi-1 depletion can induce re-replication in breast cancer cells, lead to gene amplification and stimulate tumor growth. We showed earlier that the depletion of Emi-1 induced re-replication and activated the checkpoint pathway in several breast cancer cell lines. However, we didn't observe any difference on cell growth after methotrexate (MTX) inhibition, as an indicator of gene amplification, between control and re-replicated cells, with or without the inhibition of checkpoint and apoptosis pathways. We didn't observe significant difference in tumor growth in xenograft experiments using those cells. In a separate study, we found that re-replication in colon cancer cells could activate not only apoptosis but also cellular senescence. So we hypothesize that re-replicated cells underwent senescence before we could detect any gene amplification phenotype. To test this hypothesis, we tried to inhibit the senescence pathway by depleting several known important genes. However, those genes are not essential for senescence activation. Further studies are necessary to address the issue.