Proteomics on malignant pleural effusions reveals ERα loss in metastatic breast cancer associates with SGK1NDRG1 deregulation

Author:

Mayayo‐Peralta Isabel1,Debets Donna O.2,Prekovic Stefan1,Schuurman Karianne1,Beerthuijzen Suzanne1,Almekinders Mathilde3,Sanders Joyce3,Moelans Cathy B.4,Saleiro Sandra5,Wesseling Jelle367,van Diest Paul J.4,Henrique Rui8910ORCID,Jerónimo Carmen8910ORCID,Altelaar Maarten2ORCID,Zwart Wilbert111ORCID

Affiliation:

1. Division of Oncogenomics, Oncode Institute The Netherlands Cancer Institute Amsterdam The Netherlands

2. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences Utrecht University and Netherlands Proteomics Centre The Netherlands

3. Department of Pathology The Netherlands Cancer Institute Amsterdam The Netherlands

4. Department of Pathology University Medical Center Utrecht The Netherlands

5. Lung Cancer Clinics Portuguese Oncology Institute of Porto Portugal

6. Division of Molecular Pathology The Netherlands Cancer Institute Amsterdam The Netherlands

7. Department of Pathology Leiden University Medical Center The Netherlands

8. Cancer Biology and Epigenetics Group Research Center of the Portuguese Oncology Institute‐Porto Portugal

9. Department of Pathology Portuguese Oncology Institute of Porto Portugal

10. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS) University of Porto Portugal

11. Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering Eindhoven University of Technology The Netherlands

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.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Publisher

Wiley

Subject

Cancer Research,Genetics,Molecular Medicine,General Medicine,Oncology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3