Phenotypic characterisation of breast cancer: the role of CDC42.

PURPOSE: The molecular landscape of breast cancer (BC), especially of the Luminal A subtype, remains to be fully delineated. Transcriptomic data show that Luminal A tumours are enriched for aberrant expression of genes in the cell division control 42 homolog (CDC42) pathway. This study aims to investigate the protein expression of CDC42 in BC and assess its clinicopathological significance. METHODS: Expression of CDC42 protein was examined by immunohistochemistry on tissue microarrays in a well-characterised cohort of 895 early-stage (I-IIIa) primary invasive BCs. RESULTS: CDC42 expression was observed in both the cytoplasm and the nucleus of BC cells. High nuclear CDC42 expression demonstrated a significant correlation with ER-positive, low-grade tumours and was more common in the lobular histological subtype (all p < 0.001). In contrast, cytoplasmic CDC42 showed increased expression in the ductal subtype (p < 0.001) and correlated with negative prognostic features such as larger size, higher grade (p < 0.05) and higher Ki67 labelling index (p = 0.001). Nuclear CDC42 expression was associated with a longer BC-specific survival in all cases (p = 0.025) and in luminal ER-positive tumours (p = 0.011). In multivariate analyses including size, grade, lymph node stage and intrinsic subtype, CDC42 was an independent prognostic factor (p = 0.032). CONCLUSION: The results indicate that CDC42 is an important molecule in luminal BC, with prognostic significance.

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

BACKGROUND: The 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. METHODS: The 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). FINDINGS: On χ(2) 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. INTERPRETATION: These 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. FUNDING: Pathological Society of Great Britain and Northern Ireland, National Institute for Health Research.