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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Hormonal / pharmacology*
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Antineoplastic Agents, Hormonal / therapeutic use
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Aromatase Inhibitors / pharmacology
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Aromatase Inhibitors / therapeutic use
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Breast / pathology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology*
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Cell Movement / drug effects
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Cell Movement / genetics
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Cytoskeleton / genetics
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Cytoskeleton / pathology*
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Drug Resistance, Neoplasm / genetics
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Enhancer Elements, Genetic / genetics
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Epigenesis, Genetic
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Estrogen Receptor alpha / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Keratins, Type II / genetics*
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Keratins, Type II / metabolism
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MCF-7 Cells
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / pathology
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Neoplasm Recurrence, Local / drug therapy
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Neoplasm Recurrence, Local / genetics
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Neoplasm Recurrence, Local / mortality
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Neoplasm Recurrence, Local / pathology*
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Prognosis
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Protein Domains / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism*
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Up-Regulation
Substances
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Antineoplastic Agents, Hormonal
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Aromatase Inhibitors
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ESR1 protein, human
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Estrogen Receptor alpha
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KRT80 protein, human
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Keratins, Type II
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SREBF1 protein, human
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Sterol Regulatory Element Binding Protein 1