The triple negative breast cancer (TNBC) subtype accounts for approximately 15% of breast cancer diagnoses. It is more aggressive and diagnosed in younger women than other subtypes. TNBC tumours do not express the estrogen receptor (ER) or progesterone receptor (PR) and do not overexpress human epidermal growth factor 2 (HER2). These three receptors are the major targets for endocrine and biological therapies, meaning TNBC patients are left with limited treatment options and a poor prognosis. It is therefore important to identify novel therapeutic targets in TNBC to improve patient outcome.
ER and PR are two of 48 human nuclear receptors. Nuclear receptors are ligand activated transcription factors that regulate a vast range of physiological processes. Aberrant nuclear receptor signalling is implicated in various disease states, including many types of cancer. It was thus hypothesised that other nuclear receptors may offer therapeutic targets for TNBC patients. Initial analysis identified the glucocorticoid receptor (GR) was (i) differentially expressed in TNBC compared to the normal breast and (ii) patient data showed that high expression of GR was predictive of a worse prognosis.
In general, GR has anti-inflammatory and anti-tumourigenic roles. However, high expression of GR in TNBC was found to be correlated with poor relapse-free survival, suggesting a functional switch in GR behaviour in these tumours. It is therefore proposed that modulation of GR may offer a novel therapeutic strategy for patients with TNBC.
This study employed the use of monolayer and 3D cell culture models to investigate the function of GR in TNBC. Ligand activation of GR was found not to have any pro-proliferative effect on TNBC cell lines but GR knockdown had anti-proliferative and pro-apoptotic effects. It was also noted in the high-GR cell line, there was basal activation of GR target genes observed pointing to ligand-independent activation of GR.
A bioinformatics approach utilised public deposit-database datasets to predict transcription factors and cell signalling pathways that interact with GR in TNBC to promote tumour growth resulting in poor patient survival and preliminary studies into the effects of GR modulation on metabolism and the relationship of GATA6 and GR in TNBC were carried out.
Collectively, these observations identify a novel non-ligand function of GR in breast cancer.
