2. Academic Validation
  3. Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer

Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer

  • Genes Dev. 2025 Nov 5. doi: 10.1101/gad.352953.125.
Chunlei Shao 1,  Alexandra Indeglia 1,  Maya Foster 1 2,  Kaitlyn Casey 1 3,  Jessica Leung 1,  Shirin R Modarai 4,  Julia I-Ju Leu 5,  Bryant Duong 1,  Anne-Marie Mes-Masson 6,  Jennifer Sims-Mourtada 4,  Noam Auslander 1,  Ronny Drapkin 7,  Benjamin G Bitler 8,  Nan Zhang 1,  Maureen E Murphy 9
Affiliations

Affiliations

  • 1 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • 2 Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 3 Graduate Group in Cancer Biology, St Joseph's University, Philadelphia, Pennsylvania 19131, USA.
  • 4 Helen F. Graham Cancer Center and Research Institute, ChristianaCare, Newark, Delaware 19713, USA.
  • 5 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 6 Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Institut du Cancer de Montréal, Université de Montréal, Montréal, Québec H2X 0A9, Canada.
  • 7 Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 8 Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
  • 9 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA; [email protected].
PMID: 41193244 DOI: 10.1101/gad.352953.125
Abstract

High-grade serous ovarian Cancer (HGSOC) is a highly lethal gynecologic malignancy in women. Women diagnosed with HGSOC initially respond to chemotherapy, but there is a >80% rate of relapse. There is thus a significant unmet need for new therapeutic targets for HGSOC. Estrogen receptor α (ERα) is a particularly attractive candidate, as ∼70% of HGSOC tumors stain positively for ERα and there are approved inhibitors that show limited toxicity. However, unlike the case for breast Cancer, endocrine therapy for HGSOC has not shown consistently promising results. In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

Keywords

endocrine therapy; estrogen receptor; mutant p53; ovarian cancer.

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