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 del Rio Hernandez, Charles Coombes, Giancarlo Pruneri, Adrian Lim, Fernando Calvo, Luca Magnani

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number2115
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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