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Nat Commun. 2019 May 9;10(1):2115. doi: 10.1038/s41467-019-09676-y.

SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer.

Author information

1
Department of Surgery and Cancer, Imperial College London, London, UK.
2
Division of Cancer Biology, Tumour Microenvironment Team, Institute of Cancer Research, London, UK.
3
MRC Molecular Haematology Unit, Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
4
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
5
2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
6
European Institute of Oncology, Milan, Italy.
7
Faculty of Engineering, Department of Bioengineering, Imperial College London, London, UK.
8
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Rimini, Italy.
9
Department of Chemistry, Imperial College London, London, UK.
10
Histopathology Department, Imperial College London, Charing Cross Hospital NHS Trust, London, UK.
11
ECMC Imperial College. Department of Surgery and Cancer, Imperial College London, London, UK.
12
Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, School of Medicine, Milan, Italy.
13
Division of Cancer Biology, Tumour Microenvironment Team, Institute of Cancer Research, London, UK. calvof@unican.es.
14
Instituto de Biomedicina y Biotecnologia de Cantabria, Santander, Spain. calvof@unican.es.
15
Department of Surgery and Cancer, Imperial College London, London, UK. l.magnani@imperial.ac.uk.

Abstract

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

PMID:
31073170
PMCID:
PMC6509342
DOI:
10.1038/s41467-019-09676-y
[Indexed for MEDLINE]
Free PMC Article

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