SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer.
Ylenia PeroneAaron J FarrugiaAlba Rodríguez-MeiraBalázs GyőrffyCharlotte IonAndrea UggettiAntonios ChronopoulosPasquale MarrazzoMonica FaronatoSami ShoushaClaire DaviesJennifer H SteelNaina PatelArmando Del Rio HernandezCharles CoombesGiancarlo PruneriAdrian LimFernando CalvoLuca MagnaniPublished in: Nature communications (2019)
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.
Keyphrases
- binding protein
- poor prognosis
- induced apoptosis
- end stage renal disease
- cell cycle arrest
- dna methylation
- chronic kidney disease
- artificial intelligence
- signaling pathway
- squamous cell carcinoma
- free survival
- gene expression
- cell proliferation
- ejection fraction
- long non coding rna
- newly diagnosed
- small cell lung cancer
- transcription factor
- high resolution
- peritoneal dialysis
- breast cancer cells
- estrogen receptor
- cell death
- endoplasmic reticulum
- risk assessment
- patient reported outcomes
- combination therapy
- escherichia coli
- patient reported
- data analysis
- drug induced