Mechanism and Predictive Role of NUB1 Protein in Oestrogen Receptor Pathway of FEC-Treated Breast Cancer Patients

Introduction: NEDD8 Ultimate Buster 1 (NUB1) is a regulator of the cell cycle and a prognostic marker in cancer patients. However, its role in breast cancer (BC) and its response to 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) treatment remain unclear. This study investigated NUB1's predictive value in FEC treatment and its mechanistic interaction with the oestrogen receptor (ER) in BC. Methods: MDA-MB-231 and MCF-7 cells were treated with FEC and analysed via flow cytometry for cell cycle distribution. Western blotting assessed NUB1 and ERα expression, while immunohistochemistry was conducted on a retrospective cohort (n = 85) from Malaysian hospitals to evaluate the clinical significance of NUB1 expression. Results: FEC treatment induced S and G2 phase cell cycle arrest in MDA-MB-231 cells (p = 0.04 and p = 0.02, respectively), accompanied by NUB1 upregulation. In MCF-7 cells, G2/M arrest was observed (p = 0.01), with reduced ERα expression and increased NUB1 levels in both cell lines. Lower cytoplasmic NUB1 expression was associated with poorer overall survival (OS) (HR = 0.60; 95% CI = 0.32-1.11; p = 0.10). Patients with low NUB1 and low ER expression showed the worst OS outcomes. Discussion: NUB1 upregulation following FEC treatment led to cell cycle arrest in ER-negative cells, whereas ERα suppression failed to induce S-phase arrest in ER-positive cells. Low NUB1 expression predicted poorer OS and increased BC recurrence. Conclusions: By integrating in vitro and clinical data, this study suggests that NUB1 may serve as a predictive biomarker in FEC-treated breast cancer. Larger studies are needed to validate and establish NUB1's predictive role in FEC-treated patients.