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

Abstract

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.

• Authors: Andrew R Green, Mohammed A Aleskandarany, Devika Agarwal, Somaia Elsheikh, Christopher C Nolan, Maria Diez-Rodriguez, R Douglas Macmillan, Graham R Ball, Carlos Caldas, Srinivasan Madhusudan, Ian O Ellis, Emad A Rakha
• Journal: British journal of cancer (Br J Cancer) Vol. 114 Issue 8 Pg. 917-28 (Apr 12 2016) ISSN: 1532-1827 [Electronic] England
• PMID: 26954716 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Cyclin B1
• Cyclin E
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Receptor, ErbB-2
• Ataxia Telangiectasia Mutated Proteins

Topics

• Aged
• Ataxia Telangiectasia Mutated Proteins (genetics)
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (genetics, pathology)
• Class I Phosphatidylinositol 3-Kinases
• Cyclin B1 (genetics)
• Cyclin E (genetics)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• Endocrine Cells (physiology)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Phosphatidylinositol 3-Kinases (genetics)
• Prognosis
• Proto-Oncogene Proteins c-myc (genetics)
• RNA, Messenger (genetics)
• Receptor, ErbB-2 (genetics)