The role of BUB and CDC proteins in low-grade breast cancers

Abstract

BackgroundThe drivers of neoplasia within low-grade luminal breast cancers remain undelineated. The BUB and CDC family are among kinase genes known recently to help to identify luminal breast cancers with poorer prognosis. Additionally, other CDC kinase genes (CDC42) are associated with luminal A breast cancers with good prognosis. We aimed to investigate the role of these kinases at the protein level within low-grade luminal breast cancers. MethodsThe Nottingham Tenovus Primary Breast Cancer Series (n=1858) microarrays were immunostained for BUB (BUB1, BUB1B, BUB3) and CDC proteins (CDC2, CDC42) and expression correlated with clinicopathological and molecular variables and patient outcome (SPSS, version 22). FindingsOn χ2 analysis, cytoplasmic BUB1 and nuclear BUB3 were negatively associated with grade including pleomorphism, mitosis, and Nottingham Prognostic Index, whereas BUB1B was positively associated (p=0·05). BUB1 and BUB3 expression was positively correlated with oestrogen and progesterone receptor expression whereas BUB1B was negatively correlated (p=0·01). CDC42 had strong associations with tumour morphology within the low-grade luminal breast cancers, tubular and lobular (p=0·02). CDC42 nuclear expression revealed negative correlations with basal (CK5) and HER family biomarkers (p=0·02). By contrast, cytoplasmic CDC2 overexpression was associated with high-grade tumours (p=0·01). BUB1, BUB1B, and CDC42 showed significant associations (p=0·04) with breast-cancer-specific survival even at the 15–20-year range, indicating their long-term prognostic potential. InterpretationThese results suggest that BUB1, BUB3, and CDC42 are key kinases for low-grade luminal tumours whereas BUB1B and CDC2 kinases are preferentially expressed in high-grade disease. High protein expression of BUB1, BUB3, and CDC42 in low-grade breast cancers was associated with longer overall survival whereas lower expression resulted in poorer outcome. FundingPathological Society of Great Britain and Northern Ireland, National Institute for Health Research.