oncogenes/pathways besides her2. One may be her3 for which there are drugs
under development, and another may be TFAP2C (newly identified target)
Her2+ breast cancers seem to be even more heterogeneous than previously thought. The good news: they are finding the other targets, so more and better drugs can be developed. The best may be drugs/dietary compounds which are already approved/known, so they can be available soon.
As usual, the problem is more complex than previously thought.
Oncogene advance online publication 21 January 2013; doi: 10.1038/onc.2012.625
Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies
K-K Shiu1, D Wetterskog1, A Mackay1, R Natrajan1, M Lambros1, D Sims1, I Bajrami1, R Brough1, J Frankum1, R Sharpe1, C Marchio2, H Horlings3, F Reyal3, M van der Vijver3, N Turner1, J S Reis-Filho1, C J Lord1 and A Ashworth1
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
2Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy
3Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands
Correspondence: Professor JS Reis-Filho or Dr CJ Lord or Professor A Ashworth, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. E-mails:
Jorge.Reis-Filho@icr.ac.uk or
Chris.Lord@icr.ac.uk or
Alan.Ashworth@icr.ac.uk
Received 29 May 2012; Revised 4 November 2012; Accepted 14 November 2012
Advance online publication 21 January 2013
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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.
researchers determine that most her2+ breast cancers seem to be addicted to other
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