Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity

• Published in: PLoS genetics Vol. 12; no. 9; p. e1006279
• Main Authors: Mair, Barbara, Konopka, Tomasz, Kerzendorfer, Claudia, Sleiman, Katia, Salic, Sejla, Serra, Violeta, Muellner, Markus K, Theodorou, Vasiliki, Nijman, Sebastian M B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02-09-2016; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell cycle; Clinical medicine; Colleges & universities; Disease-Free Survival; Drug interactions; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic; Estrogens - genetics; Estrogens - metabolism; Female; Frameshift Mutation; GATA3 Transcription Factor - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genomics; Health aspects; Histocompatibility Antigens - genetics; Histone-Lysine N-Methyltransferase - genetics; Humans; MCF-7 Cells; Medical research; Medicine; Medicine and Health Sciences; Mutation; Small Molecule Libraries - chemistry; Small Molecule Libraries - therapeutic use; Austria
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006279

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.