title: Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity.
abstract: Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis, and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood, breast cancer gene. We identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. Furthermore, we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation. Our findings reveal important insights into mutant GATA3 function and breast cancer, provide the first potential therapeutic strategy and suggest that dual tumour suppressive and oncogenic activities are more widespread than previously appreciated.
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors: Barbara
authors: 0000-0001-6982-2529
authors: B
authors: Mair
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors: Tomasz
authors: 0000-0003-3042-4712
authors: T
authors: Konopka
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Claudia
authors: C
authors: Kerzendorfer
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Katia
authors: 0000-0001-5808-1913
authors: K
authors: Sleiman
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors: Sejla
authors: S
authors: Salic
authors: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Violeta
authors: V
authors: Serra
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Markus K
authors: MK
authors: Muellner
authors: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece.
authors: Vasiliki
authors: 0000-0003-1614-700X
authors: V
authors: Theodorou
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors: Sebastian M B
authors: SM
authors: Nijman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D050990:GATA3 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D004967:Estrogens; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D006649:Histocompatibility Antigens; D054852:Small Molecule Libraries; C455847:EHMT1 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase