RESEARCH ARTICLE The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells Sean W Fanning1, Rinath Jeselsohn2,3, Venkatasubramanian Dharmarajan4, Christopher G Mayne5, Mostafa Karimi6, Gilles Buchwalter2, Rene´ Houtman7, Weiyi Toy8, Colin E Fowler1, Ross Han1, Muriel Laine´ 1, Kathryn E Carlson9, Teresa A Martin9, Jason Nowak3, Jerome C Nwachukwu10, David J Hosfield1, Sarat Chandarlapaty8, Emad Tajkhorshid5, Kendall W Nettles4, Patrick R Griffin4, Yang Shen6, John A Katzenellenbogen9, Myles Brown2,3, Geoffrey L Greene1* 1Ben May Department for Cancer Research, University of Chicago, Chicago, United States; 2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; 4Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States; 5Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States; 6Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States; 7PamGene International BV, ‘s-Hertogenbosch, The Netherlands; 8Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States; 9Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States; 10Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States *For correspondence:
[email protected] Abstract Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) gene ligand- Competing interest: See binding domain (LBD) represent a recognized mechanism of acquired resistance.