Mechanistic and Clinical Evidence Supports a Key Role for Cell Division Cycle Associated 5 (CDCA5) as an Independent Predictor of Outcome in Invasive Breast Cancer

SIMPLE SUMMARY: Breast cancer (BC) exhibits substantial genetic and clinical heterogeneity. Given the importance of understanding the molecular mechanisms underlying cancer cell division, migration, and evasion of apoptosis to develop novel therapies, identifying novel prognostic biomarkers is critical for accurate predictions of BC patient outcomes and treatment decisions. The goal of this retrospective study was to evaluate the potential prognostic value of the Cell Division Cycle Associated 5 (CDCA5), which is a member of the cyclin dependent kinase family and plays an important role in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway involving in cell division, cancer cell migration, and apoptosis. Our findings emphasize the significance of CDCA5 expression and its role in cell migration and evading apoptosis in BC tumor progression and worse patients’ clinical outcome. Further functional investigations are warranted to understand the crosstalk between cancer cell migration and evasion of apoptosis underlying mechanisms for targeted therapy development. ABSTRACT: Background: Cell Division Cycle Associated 5 (CDCA5) plays a role in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signalling pathway involving cell division, cancer cell migration and apoptosis. This study aims to assess the prognostic and biological value of CDCA5 in breast cancer (BC). Methods: The biological and prognostic value of CDCA5 were evaluated at mRNA (n = 5109) and protein levels (n = 614) utilizing multiple well-characterized early stage BC cohorts. The effects of CDCA5 knockdown (KD) on multiple oncogenic assays were assessed in vitro using a panel of BC cell lines. Results: this study examined cohorts showed that high CDCA5 expression was correlated with features characteristic of aggressive behavior and poor prognosis, including the presence of high grade, large tumor size, lymphovascular invasion (LVI), hormone receptor negativity and HER2 positivity. High CDCA5 expression, at both mRNA and protein levels, was associated with shorter BC-specific survival independent of other variables (p = 0.034, Hazard ratio (HR) = 1.6, 95% CI; 1.1–2.3). In line with the clinical data, in vitro models indicated that CDCA5 depletion results in a marked decrease in BC cell invasion and migration abilities and a significant accumulation of the BC cells in the G2/M-phase. Conclusions: These results provide evidence that CDCA5 plays an important role in BC development and metastasis and could be used as a potential biomarker to predict disease progression in BC.