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

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

  • Cancer Res. 2024 Dec 16;84(24):4283-4297. doi: 10.1158/0008-5472.CAN-24-0013.
Carolina Gemma 1 Chun-Fui Lai 1 Anup K Singh 1 Antonino Belfiore 2 3 Neil Portman 4 Heloisa Z Milioli 4 Manikandan Periyasamy 1 Sara Raafat 5 6 Alyssa J Nicholls 1 Claire M Davies 7 Naina R Patel 7 Georgia M Simmons 1 Hailing Fan 1 Van T M Nguyen 1 Luca Magnani 1 Emad Rakha 5 6 Lesley-Ann Martin 8 Elgene Lim 4 9 R Charles Coombes 1 Giancarlo Pruneri 2 3 Laki Buluwela 1 Simak Ali 1
Affiliations

Affiliations

  • 1 Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom.
  • 2 Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
  • 3 School of Medicine, University of Milan, Milan, Italy.
  • 4 Garvan Institute of Medical Research, Darlinghurst, Australia.
  • 5 Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, United Kingdom.
  • 6 Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
  • 7 Department of Surgery and Cancer, ECMC Imperial College, Imperial College London, Hammersmith Campus, London, United Kingdom.
  • 8 Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom.
  • 9 St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia.
Abstract

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.

Figures
Products