Induction of the TEAD Coactivator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.

Autor:	Gemma C; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Lai CF; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Singh AK; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Belfiore A; Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.; School of Medicine, University of Milan, Milan, Italy., Portman N; Garvan Institute of Medical Research, Darlinghurst, Australia., Milioli HZ; Garvan Institute of Medical Research, Darlinghurst, Australia., Periyasamy M; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Raafat S; Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, United Kingdom.; Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Nottingham, United Kingdom., Nicholls AJ; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Davies CM; Department of Surgery and Cancer, ECMC Imperial College, Imperial College London, Hammersmith Campus, London, United Kingdom., Patel NR; Department of Surgery and Cancer, ECMC Imperial College, Imperial College London, Hammersmith Campus, London, United Kingdom., Simmons GM; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Fan H; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Nguyen VTM; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Magnani L; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Rakha E; Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, United Kingdom.; Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Nottingham, United Kingdom., Martin LA; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom., Lim E; Garvan Institute of Medical Research, Darlinghurst, Australia.; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia., Coombes RC; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Pruneri G; Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.; School of Medicine, University of Milan, Milan, Italy., Buluwela L; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom., Ali S; Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Dec 16; Vol. 84 (24), pp. 4283-4297.
DOI:	10.1158/0008-5472.CAN-24-0013
Abstrakt:	Resistance to endocrine therapies (ET) is common in estrogen receptor (ER)-positive breast cancer, and most relapsed patients die with ET-resistant disease. Although 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 profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders, such as fulvestrant, promote expression of vestigial-like 1 (VGLL1), a coactivator for TEF-1 and AbaA domain (TEAD) transcription factors. VGLL1, acting via TEADs, promoted the expression of genes that drive the growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1-TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent the 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. Significance: Transcriptional reprogramming mediated by the upregulation of the TEAD coactivator VGLL1 confers resistance to estrogen receptor degraders in breast cancer but provides alternative therapeutic options for this clinically important patient group. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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