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

Isabel Mayayo-Peralta, Donna O. Debets, Stefan Prekovic, Karianne Schuurman, Suzanne Beerthuijzen, Mathilde Almekinders, Joyce Sanders, Cathy B. Moelans, Sandra Saleiro, Jelle Wesseling, Paul J. van Diest, Rui Henrique, Carmen Jerónimo, Maarten Altelaar (Corresponding author), Wilbert Zwart (Corresponding author)

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Abstract

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 (ERα), 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 ERα-positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα-conversion. It remains unclear whether ERα-converted cancers are biologically similar to bona fide ERα-negative disease and which signalling cascades compensate for ERα loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ERα loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 BCa patients, comparing ERα-positive, ERα-converted and ERα-negative cases. Our data revealed that the loss of ERα-dependency in this metastatic site leads to only a partial switch to an ERα-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 ERα-converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ERα-dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.

Original languageEnglish
Pages (from-to)156-169
Number of pages14
JournalMolecular Oncology
Volume18
Issue number1
DOIs
Publication statusPublished - Jan 2024

Funding

This work was supported the Netherlands Organization for Scientific Research (NWO-VIDI-016.156.401 to WZ). We thank members of the Zwart and Bergman labs for valuable feedback, suggestions and input. We thank the Core Facility Molecular Pathology and Biobanking (CFMPB) from NKI for technical support and sample processing. Finally, we would like to thank all the patients and clinical staff who were involved in this study.

FundersFunder number
NKI-AVL Core Facility Molecular Pathology and Biobanking
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO‐VIDI‐016.156.401

    Keywords

    • breast cancer metastasis
    • NDRG1
    • oestrogen receptor
    • proteomics
    • receptor conversion
    • SGK1

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