title: Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.
abstract: Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes. Some of these genes may have important roles in influencing clinical outcome, and could represent genetic dependencies in ERBB2+ve cancers and therefore potential therapeutic targets. Here, we describe an integrated genomic, gene expression and functional analysis to determine whether the genes present within amplicons are critical for the survival of ERBB2+ve breast tumour cells. We show that only a fraction of the ERBB2-amplified breast tumour lines are truly addicted to the ERBB2 oncogene at the mRNA level and display a heterogeneous set of additional genetic dependencies. These include an addiction to the transcription factor gene TFAP2C when it is amplified and overexpressed, suggesting that TFAP2C represents a genetic dependency in some ERBB2+ve breast cancer cells.
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: K-K
authors: KK
authors: Shiu
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: D
authors: D
authors: Wetterskog
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: A
authors: A
authors: Mackay
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: R
authors: R
authors: Natrajan
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: M
authors: M
authors: Lambros
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: D
authors: D
authors: Sims
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: I
authors: I
authors: Bajrami
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: R
authors: R
authors: Brough
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: J
authors: J
authors: Frankum
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: R
authors: R
authors: Sharpe
authors: Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy.
authors: C
authors: C
authors: Marchio
authors: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: H
authors: H
authors: Horlings
authors: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: F
authors: F
authors: Reyal
authors: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: M
authors: M
authors: van der Vijver
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: N
authors: N
authors: Turner
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: J S
authors: JS
authors: Reis-Filho
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: C J
authors: CJ
authors: Lord
authors: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors: A
authors: A
authors: Ashworth
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D061986:MCF-7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D050656:Transcription Factor AP-2; C493679:TFAP2C protein, human; C508053:ERBB2 protein, human