| dc.description.abstract | ABSTRACT Background: Breast cancer in young women (BCYW) is an aggressive disease with devastating consequences. Studies suggest that patients diagnosed with breast cancer before the age of 40 years have poorer 5-year survival. The biological mechanisms underlying this behaviour are yet to be fully elucidated. Methods: An in-silico integrative, enrichment and survival analysis across multiple datasets was undertaken to identify genes and biological processes associated with BCYW. Immunohistochemical analysis of identified targets was performed on patient samples. Functional impact on cell proliferation, cell cycle and DNA damage was assessed in four breast cancer cell lines (HC1973; MCF7; MDA-MB-468; SKBR3). Results: In-silico analysis identified upregulation of SMC4, KIF4A and GPLD1, with downregulation of WLS in tumours from young patients compared to reduction mammoplasty. Poor survival was identified in young patients (≤40 years) with low expression of SMC4 (p = 0.04), KIF4A (p = 0.006) and GPLD1 (p = 0.004) and high expression of WLS (0.06). SMC4 and KIF4A were associated with aggressive behaviour across all datasets. In tissues, high KIF4A expression correlated with high Ki67 (p = 0.04) while high SMC4 correlated with Luminal A molecular subtype (p = 0.05). In vitro, knockdown of KIF4A increased cell proliferation in MDA-MB-468 and MCF7 breast cancer cells and similar trend in proliferation in SMC4 knockdown in same cells; resulted in increased G2/M fraction in MCF7 cells (KIF4A knockdown) and all breast cancer cell lines with SMC4 knockdown. A trend towards increased DNA damage in KIF4A and SMC4 knockdown SKBR3 cells was seen. Conclusions: This study identified SMC and KIF4A as genes associated with aggressive behaviour of BCYW and found expression correlates with clinicopathologic features of tumours. It demonstrates that KIF4A and SMC4 affects proliferation and cell cycle disruption in a tumour cell-type specific manner and suggests that disrupted expression can promote DNA damage in vitro. Their clinical utility as prognostic markers and potential therapeutic targets warrants further investigation. | en_US |
