Proteomics on malignant pleural effusions reveals ER loss in metastatic breast cancer associates with SGK1-NDRG1 deregulation

Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision-making. The majority of primary tumours are positive for oestrogen receptor alpha (ER alpha), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one-third of patients with ER alpha-positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ER alpha expression after endocrine treatment, known as ER alpha-conversion. It remains unclear whether ER alpha-converted cancers are biologically similar to bona fide ER alpha-negative disease and which signalling cascades compensate for ER alpha loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ER alpha loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 BCa patients, comparing ER alpha-positive, ER alpha-converted and ER alpha-negative cases. Our data revealed that the loss of ER alpha-dependency in this metastatic site leads to only a partial switch to an ER alpha-negative molecular phenotype, with preservation of a luminal-like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum/glucocorticoid regulated kinase 1 (SGK1), in ER alpha-converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ER alpha-dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.