Cdc20 and securin overexpression predict short-term breast cancer survival

According to present knowledge, the most essential steps in cell division occur in metaphase–anaphase transition during chromosome segregation (Yamanaka et al, 2012). Accuracy of chromosome segregation is dependent on mitotic spindle assembly checkpoint (SAC), which delays anaphase initiation until all sister chromatids are correctly attached to the mitotic spindle by their kinetochores (Musacchio and Salmon, 2007; Kim and Yu, 2011). Inappropriately functioning SAC has been linked to chromosomal instability (CIN) and aneuploidy (Jallepalli and Lengauer, 2001; Suijkerbuijk and Kops, 2008). The key event of SAC is inhibition of anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets degradation of securin and cyclin B1 when activated by Cdc20. Activation of the APC–Cdc20 complex and degradation of securin and cyclin B1 then mark anaphase onset in normally regulated cell division. The checkpoint proteins, such as Mad1, Mad2, BubR1, Bub1, Bub3, Mps1 and AuroraB form a complex signalling network that inhibits APC/C-Cdc20 (Musacchio and Salmon, 2007; Kim and Yu, 2011). Mad2 and BubR1 function in APC/C inhibition both independently and as a part of a more potent inhibitory complex with Bub3 and Cdc20, the so called mitotic checkpoint complex (MCC) (Sudakin et al, 2001; Tang et al, 2001; Fang, 2002). Human Cdc20/p55cdc, a homologue of Saccharomyces cerevisiae cell division cycle 20 protein, is one of the most important components of the mammalian cell-cycle mechanism (Weinstein et al, 1994; Weinstein, 1997). As an integral part of the SAC, Cdc20 ensures that anaphase proceeds only when the centromeres of all sister chromatids are lined up in the metaphase plate and properly attached to microtubules. Recently Cdc20 overexpression has been associated with inappropriately functioning SAC and aneuploidization in oral cancer (Mondal et al, 2007). High Cdc20 expression has been reported in several human cancer cell lines (Kim et al, 2005b; Iacomino et al, 2006; Thirthagiri et al, 2007; Yuan et al, 2006; Jiang et al, 2011; Chang et al, 2012) and several carcinoma tissues (Kim et al, 2005b; Ouellet et al, 2006; Kidokoro et al, 2008; Jiang et al, 2011). High Cdc20 expression has also been linked to poor prognosis in lung (Kato et al, 2012), oral squamous cell (Moura et al, 2013), bladder (Choi et al, 2013), colon (Wu et al, 2013) and pancreatic (Chang et al, 2012) carcinomas. Overexpression of securin has been associated with unfavourable prognosis in multiple cancer types (Vlotides et al, 2007; Salehi et al, 2008). In our previous work, we have shown that high securin expression predicts aneuploidy and unfavourable prognosis in human breast cancer (Karra et al, 2012). Active securin binds to and inhibits separase activity, whereas degradation of securin releases separase to cleave centromeric cohesion at anaphase onset – a process dependent on APC-Cdc20 activation (Nasmyth, 1999; Nasmyth et al, 2000). Thus, securin seems to have an anaphase promoting quality, as the prior interaction with securin is needed for separase to function properly (Kumada et al, 1998; Jensen et al, 2001). Both overexpression and lack of securin have been suggested to compromise chromosomal stability (Jallepalli et al, 2001; Bernal et al, 2002; Yu et al, 2003; Kim et al, 2005a, 2007). Recently a single mutation in securin was shown to induce CIN (Mora-Santos et al, 2013). The complete role of securin in diseased cells is still not settled but multifactorial mechanisms in aneuploidy, apoptosis, angiogenesis, tumour cell transformation and microenvironment regulation and role in DNA repair checkpoint have been suggested (Tfelt-Hansen et al, 2006; Vlotides et al, 2007; Salehi et al, 2008). Increasing evidence suggests clinically significant applications of securin in association with disease outcome and as a biomarker for subsequent therapeutic interventions (Solbach et al, 2005; Cho-Rok et al, 2006; Kakar and Malik, 2006; Panguluri et al, 2008). The purpose of this study is to evaluate the significance of Cdc20 independently and in combination with securin as a prognostic marker for breast cancer patients. The study is based on a material of 445 breast cancer patients with up to 22 years of follow-up (mean follow-up 10.0 years). Our findings suggest that the combination of high Cdc20 and securin expression identify a specific group of patients with aneuploid cell type and extremely short breast cancer survival, in average 2.4 years after diagnosis (median 2.7 years). In our material, Cdc20 and securin overexpression was associated with aggressive cell morphology and triple-negative breast carcinoma subtype.