ANTI-TUMOUR TREATMENT 17q12-21 – The pursuit of targeted therapy in breast cancer R.W. Glynn, N. Miller * , M.J. Kerin Department of Surgery, Clinical Science Institute, National University of Ireland, Costello Road, Galway, Ireland article info Article history: Received 23 October 2009 Received in revised form 8 December 2009 Accepted 9 December 2009 Keywords: HER2/neu TOP2A GRB7 STARD3 RARA HER2/neu amplicon summary Purpose: Identification of HER2/neu, and the subsequent development of targeted therapy for patients who over-express it, has revolutionized their management. Research has since focused on the area of chromosome 17 in which HER2/neu is located in order to identify other genes in the vicinity. The aims of this review are, firstly, to discuss current thinking in relation to the role of these genes in the patho- genesis of breast cancer and, secondly, to examine how this evidence may be assimilated such that new forms of targeted therapy can be developed. Experimental design: This review discusses the evidence in relation to 4 genes located at the HER2/neu amplicon, namely TOP2A, GRB7, STARD3 and RARA. Results: TOP2A has aroused particular interest as over-expression of its protein has been shown to cor- relate, both with amplification of HER2/neu, and with response to anthracycline-based chemotherapeutic agents in breast cancer. GRB7 is included on Oncotype DXtm, and has recently been implicated in gastric and oesophageal cancer. STARD3 and RARA also hold clinical relevance, the former having been shown to function in steroidogenesis and therefore implicated in hormone-receptor-positive breast cancer. Finally, RARA may be the key to unlocking the problem of resistance to all-trans retinoic acid (ATRA) in breast cancer sufferers; this treatment has previously been demonstrated to induce remission in over 80% of patients with acute promyelocytic leukaemia (APML). Conclusion: These genes hold potential as therapeutic targets, and warrant further investigation as we move towards our goal of individually tailored therapeutic strategies in breast cancer. Ó 2009 Published by Elsevier Ltd. Introduction The HER2/neu oncogene encodes for a 185 kd glycoprotein, and is one of a family of Epidermal Growth Factor Receptors; EGFR (HER1 or ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). These receptors form a sub-grouping of a ‘super-family’ of Receptor Tyrosine Kinases (RTKs), which are involved in ‘‘funda- mental cellular processes such as proliferation, migration, metabo- lism, differentiation and survival, as well as those that regulate intercellular communication during development”. 1 There is no known ligand for HER2/neu itself, but it would appear that the extracellular component of this glycoprotein acts as a ligand for other members of its family, and it is postulated, therefore, that HER2/neu plays a key role in modulation of signal transduction in the aftermath of this binding process. 2 Approximately 20–30% of newly diagnosed breast cancers are found to over-express HER2/neu. Amplification of this gene, located on chromosome 17, with concomitant over-expression, is associated with a more aggressive form of malignancy and poorer outcome. 3 Since this relationship with outcome was first elucidated in 1987, interest in HER2/neu has largely been focused on the development of tar- geted therapy for HER2/neu-positive patients. This interest culmi- nated in the development of the anti-HER2/neu monoclonal antibody trastuzumab (Herceptin™), and its licensing for use in women with HER2/neu-positive breast cancer in 1998 (Fig. 1). Trastuzumab targets the extracellular domain of the HER2/neu molecule, 1 and has been demonstrated to significantly improve disease-free survival when given in conjunction with chemother- apy, 4,5 in those women who over-express the HER2/neu gene. In- deed, a recent study by Smith et al., 6 expanding on the original work of the Herceptin Adjuvant (HERA) Study, 4 has demonstrated an absolute overall survival benefit of 2.7% at three years [Hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.47–0.91; P = 0.0115]. 6 Because positive HER2/neu status determines the indication for trastuzumab, it is important to use simple, accurate, widely appli- cable and reproducible methods to screen tumours for gene ampli- fication and/or over-expression. The two methods which are currently in clinical use for determining HER2/neu status are im- muno-histochemical analysis (IHC) for the detection of protein expression and, fluorescent in situ hybridisation (FISH), which is a quantitative method for detection of gene amplification. Whilst 0305-7372/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.ctrv.2009.12.007 * Corresponding author. Tel.: +353 91 524390; fax: +353 91 494509. E-mail addresses: ronanglynn@doctors.org.uk (R.W. Glynn), nicola.miller@ nuigalway.ie (N. Miller), michael.kerin@nuigalway.ie (M.J. Kerin). Cancer Treatment Reviews 36 (2010) 224–229 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv