| Autor: |
Gemma C; Imperial College London, London, United Kingdom., Lai CF; Imperial College London, London, United Kingdom., Singh AK; Imperial College London, London, United Kingdom., Belfiore A; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Portman N; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Milioli HZ; Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Periyasamy M; Imperial College London, London, United Kingdom., Raafat S; Anatomic Pathology Department, Faculty of Medicine, Mansoura University, Egypt, Nottingham, United Kingdom., Nicholls AJ; Imperial College London, London, United Kingdom., Davies CM; Imperial College London, London, Select, United Kingdom., Patel NR; Imperial College London, London, United Kingdom., Simmons GM; Imperial College London, London, United Kingdom., Fan H; Imperial College London, London, United Kingdom., Nguyen VTM; Imperial College London, London, United Kingdom., Magnani L; Institute of Cancer Research, London, United Kingdom., Rakha E; University of Nottingham, Nottingham, United Kingdom., Martin LA; Institute of Cancer Research, London, United Kingdom., Lim E; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Coombes RC; Imperial College London, London, United Kingdom., Pruneri G; Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy, Italy., Buluwela L; Imperial College London, London, United Kingdom., Ali S; Imperial College London, London, United Kingdom. |
| Abstrakt: |
Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer, and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co-activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients. |
