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The majority of primary tumours are positive for oestrogen receptor alpha (ER\u03b1), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one\u2010third of patients with ER\u03b1\u2010positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ER\u03b1 expression after endocrine treatment, known as ER\u03b1\u2010conversion. It remains unclear whether ER\u03b1\u2010converted cancers are biologically similar to bona fide ER\u03b1\u2010negative disease and which signalling cascades compensate for ER\u03b1 loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ER\u03b1 loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 BCa patients, comparing ER\u03b1\u2010positive, ER\u03b1\u2010converted and ER\u03b1\u2010negative cases. Our data revealed that the loss of ER\u03b1\u2010dependency in this metastatic site leads to only a partial switch to an ER\u03b1\u2010negative molecular phenotype, with preservation of a luminal\u2010like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum\/glucocorticoid regulated kinase 1 (SGK1), in ER\u03b1\u2010converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ER\u03b1\u2010dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.<\/jats:p>","DOI":"10.1002\/1878-0261.13540","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T03:40:09Z","timestamp":1697686809000},"page":"156-169","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomics on malignant pleural effusions reveals\n                    <scp>ER\u03b1<\/scp>\n                    loss in metastatic breast cancer associates with\n                    <scp>SGK1<\/scp>\n                    \u2013\n                    <scp>NDRG1<\/scp>\n                    deregulation"],"prefix":"10.1002","volume":"18","author":[{"given":"Isabel","family":"Mayayo\u2010Peralta","sequence":"first","affiliation":[{"name":"Division of Oncogenomics, Oncode 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Saleiro","sequence":"additional","affiliation":[{"name":"Lung Cancer Clinics Portuguese Oncology Institute of Porto  Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelle","family":"Wesseling","sequence":"additional","affiliation":[{"name":"Department of Pathology The Netherlands Cancer Institute  Amsterdam The Netherlands"},{"name":"Division of Molecular Pathology The Netherlands Cancer Institute  Amsterdam The Netherlands"},{"name":"Department of Pathology Leiden University Medical Center  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"van Diest","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  The 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