Induction of the TEAD Coactivator VGLL1 by Estrogen Receptor–Targeted Therapy Drives Resistance in Breast Cancer
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.
Authors
- Van T.M. Nguyen (ORCID: https://orcid.org/0000-0002-5898-0043)
- Emad A. Rakha (ORCID: https://orcid.org/0000-0002-5009-5525)
- Claire M. Davies (ORCID: https://orcid.org/0000-0001-8651-0914)
- Luca Magnani (ORCID: https://orcid.org/0000-0002-7534-0785)
- Georgia M. Simmons
- Simak Ali (ORCID: https://orcid.org/0000-0002-1320-0816)
- Sara Raafat
- Anup K. Singh (ORCID: https://orcid.org/0000-0002-1495-2331)
- Hailing Fan
- R. Charles Coombes (ORCID: https://orcid.org/0000-0002-4811-1100)
- Carolina Gemma (ORCID: https://orcid.org/0000-0002-4890-9972)
- Giancarlo Pruneri (ORCID: https://orcid.org/0000-0002-7963-7172)
- Neil Portman (ORCID: https://orcid.org/0000-0003-0248-0258)
- Laki Buluwela (ORCID: https://orcid.org/0000-0001-6973-334X)
- Elgene Lim (ORCID: https://orcid.org/0000-0001-8065-8838)
- Naina Patel
- Manikandan Periyasamy (ORCID: https://orcid.org/0000-0001-7626-2531)
- Lesley‐Ann Martin (ORCID: https://orcid.org/0000-0002-7606-4161)
- Antonino Belfiore (ORCID: https://orcid.org/0000-0002-8011-6382)
- Chun‐Fui Lai
- Heloisa Zaccaron Milioli
- Alyssa J. Nicholls
Institutions
- Nottingham University Hospitals NHS Trust (GB)
- Garvan Institute of Medical Research (AU)
- University of Nottingham (GB)
- Institute of Cancer Research (GB)
- Mansoura University (EG)
- University of Milan (IT)
- Breast Cancer Now (GB)
- Hammersmith Hospital (GB)
- Nottingham City Hospital (GB)
- St Vincent's Clinic (AU)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Imperial College London (GB)
Publication Details
- Journal
- Cancer Research
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1158/0008-5472.can-24-0013
- Citations
- 7
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 2.28
Funders
- Cancer Research UK
- National Institute for Health and Care Research
- Imperial College London
- Imperial College Healthcare NHS Trust
- Associazione Italiana per la Ricerca sul Cancro
- Imperial Experimental Cancer Medicine Centre