MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours

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 immunuohistochemistry. 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.