Cdc27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. Here, in normal murine mammary gland epithelial cells (NMuMG), Cdc27 expression is controlled post-transcriptionally through the RNA binding protein heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1/PCBP1). shRNA-mediated knockdown of hnRNP E1 abrogates translational silencing of the Cdc27 transcript resulting in constitutive expression of Cdc27. Dysregulated expression of Cdc27 leads to premature activation of the G2/M-APC/C-Cdc20 complex resulting in the aberrant degradation of Cdh1/Fzr1, a co-factor of the G1 and late G2/M-APC/C and a substrate normally reserved for the SCF-betaTRCP ligase. Loss of Cdh1 expression and of APC/C-Cdh1 activity, upon constitutive expression of Cdc27, results in mitotic aberrations and aneuploidy in NMuMG cells. Further, tissue microarray (TMA) of breast cancer patient tumor samples reveals high Cdc27 levels compared to non-neoplastic breast tissue and a significant correlation between disease recurrence and Cdc27 expression. These results suggest that dysregulation of hnRNP E1-mediated translational regulation of Cdc27 leads to chromosomal instability and aneuploidy, and that Cdc27 expression represents a significant predictor of breast cancer recurrence. Implications: The RNA binding protein hnRNP E1 mediates translational regulation of the cell cycle regulator Cdc27 and that dysregulation of Cdc27 leads to aneuploidy. In addition, high Cdc27 expression in breast cancer patient tumor specimens significantly predicts disease recurrence, suggesting a novel role for Cdc27 as a predictor of relapse.
- Received January 18, 2016.
- Revision received April 8, 2016.
- Accepted April 11, 2016.
- Copyright ©2016, American Association for Cancer Research.