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

Ylenia Perone, Aaron J. Farrugia, Alba Rodríguez-Meira, Balázs Győrffy, Charlotte Ion, Andrea Uggetti, Antonios Chronopoulos, Pasquale Marrazzo, Monica Faronato, Sami Shousha, Claire Davies, Jennifer H. Steel, Naina Patel, Armando Rio Hernandez, Charles Coombes, Giancarlo Pruneri, Adrian Lim, Fernando Calvo () and Luca Magnani ()
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Ylenia Perone: Imperial College London
Aaron J. Farrugia: Institute of Cancer Research
Alba Rodríguez-Meira: Imperial College London
Balázs Győrffy: Hungarian Academy of Sciences
Charlotte Ion: Imperial College London
Andrea Uggetti: European Institute of Oncology
Antonios Chronopoulos: Imperial College London
Pasquale Marrazzo: University of Bologna
Monica Faronato: Imperial College London
Sami Shousha: Charing Cross Hospital NHS Trust
Claire Davies: Imperial College London
Jennifer H. Steel: Imperial College London
Naina Patel: Imperial College London
Armando Rio Hernandez: Imperial College London
Charles Coombes: Imperial College London
Giancarlo Pruneri: Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, School of Medicine
Adrian Lim: Imperial College London
Fernando Calvo: Institute of Cancer Research
Luca Magnani: Imperial College London

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09676-y

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