Abstract
1.7 million cases of breast cancer are diagnosed every year with 522,000 deaths. Molecular classifications of breast cancer have resulted in improved treatments. However, treatments for triple negative breast cancer (TNBC) are lacking. Analysis of molecular targets for TNBC is a priority. One potential candidate is androgen receptor (AR) phosphorylation. This study assessed the role of AR phosphorylation at ser81/ser515 and their two upstream effectors, cyclin-dependent kinase 1 (pCDK1) and extracellular-regulated kinase 1/2 (pERK1/2) in 332 ductal breast cancer patients by immunohistochemistry.pERK1/2 combined with AR-515 associated with improved cancer-specific survival (CSS, p = 0.038), decreased size (p = 0.001), invasive grade (p < 0.001), necrosis (p = 0.003), b-lymphocytes (p = 0.020), molecular subtype (p < 0.001) and estrogen receptor (ER)/progesterone receptor (PR)-status (p < 0.001). The cohort was therefore stratified into ER+ve and ER-ve patients. In ER+ve tumours, pERK1/2 combined with AR-515 associated with improved CSS (p = 0.038), smaller size (p = 0.004), invasive grade (p = 0.001), decreased b-lymphocytes (p = 0.013) and increased plasma cells (p = 0.048). In contrast, in TNBC patients, phosphorylation of AR-515 associated with poorer CSS (p = 0.007). pERK1/2 combined with AR-515 associated with decreased inflammation (p = 0.003), increased tumour stroma (p = 0.003) and tumour budding (p = 0.011), with trends towards decrease CSS (p = 0.065) and macrophage levels (p = 0.093).In Conclusions, AR-515 may be an important regulator of inflammation in breast cancer potential via ERK1/2 phosphorylation. AR-515 is a potential prognostic marker and therapeutic target for TNBC.
Highlights
1.7 million cases of breast cancer are diagnosed every year
androgen receptor (AR)-81 significantly correlated with nuclear CDK1 (p < 0.001) and AR-515 correlated with nuclear phosphorylated ERK1/2 (pERK1/2) (p < 0.001) as expected
This study suggests that effects of activation via phosphorylation of AR at Ser515 are subtypedependent
Summary
1.7 million cases of breast cancer are diagnosed every year. A great effort is being channelled to improve the understanding of the pathogenesis of this disease as breast cancer is highly heterogeneous with an increasing number of sub-classifications being made [2,3,4]. The majority of breast cancers comprise of luminal A and luminal B subtypes. These subtypes display oestrogen (ER) and/or progesterone receptors (PR) rendering these cancer cells susceptible to endocrine therapies e.g. antioestrogen therapies (Tamoxifen) [7, 8]. About 15% of breast cancer cases are triple receptor negative lacking expression of ER, PR or HER2 [11]
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