BACKGROUND: MYC is amplified in approximately 15% of breast cancers (BCs) and is 
associated with poor outcome. c-MYC protein is multi-faceted and participates in 
many aspects of cellular function and is linked with therapeutic response in 
BCs. We hypothesised that the functional role of c-MYC differs between molecular 
subtypes of BCs.
METHODS: We therefore investigated the correlation between c-MYC protein 
expression and other proteins involved in different cellular functions together 
with clinicopathological parameters, patients' outcome and treatments in a large 
early-stage molecularly characterised series of primary invasive BCs (n=1106) 
using immunohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for 
MYC mRNA expression and a systems biology approach utilised to identify genes 
associated with MYC in the different BC molecular subtypes.
RESULTS: High MYC and c-MYC expression was significantly associated with poor 
prognostic factors, including grade and basal-like BCs. In luminal A tumours, 
c-MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) 
and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive 
association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was 
an independent predictor of a shorter distant metastases-free survival in 
luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal 
tumours treated with ET, MYC mRNA expression was associated with BC-specific 
survival (P=0.001). In ER-positive tumours, MYC was associated with expression 
of translational genes while in ER-negative tumours it was associated with 
upregulation of glucose metabolism genes.
CONCLUSIONS: c-MYC function is associated with specific molecular subtypes of 
BCs and its overexpression confers resistance to ET. The diverse mechanisms of 
c-MYC function in the different molecular classes of BCs warrants further 
investigation particularly as potential therapeutic targets.