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Attempts to Identify New Therapeutic Targets for Triple-Negative Breast Cancer

Targeted therapy is currently available for the majority of patients with newly diagnosed breast cancer. Thus, patients with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive disease receive hormone therapy, while patients with HER2-postive disease may be treated with trastuzumab (Herceptin). For patients lacking ER/PR and HER2 overexpression however, targeted therapy is currently unavailable. Consequently, the only systemic therapy available for this subgroup of patients which have been dubbed triple-negative, is chemotherapy. Currently, there is intense interest worldwide in developing new targeted therapies for patients with triple-negative breast cancer. Workpackage 1 of the MTCI projects aims to identify such new targets with a focus on specific ADAMs and c-Met. ADAMs are proteases that activate the precursor forms of growth factors and cytokines. They thus play a critical role in cell signalling, acting upstream of receptor binding and activation. Two ADAMs have a particular relevance for malignancy, ie, ADAM10 and ADAM17. These 2 ADAMs release all the growth factors that activate the EGFR/HER family of receptors. Inhibiting these ADAMs might thus be expected to block EGFR/HER signalling and thus prevent cell growth and migration. MET is a tyrosine kinase receptor that, upon binding of its natural ligand, HGF, is phosphorylated and subsequently activates different signalling pathways involved in proliferation, motility, migration and invasion. MET has been found to be aberrantly activated in human cancer via mutation, amplification or protein overexpression. Recent findings suggest that c-Met in involved in the formation and progression of basal-type breast cancer. (Most basal-type breast cancers are also triple-negative). c-Met might thus be expected to be a good therapeutic target for treating triple-negative breast cancer. Micro (mi)RNAs are small non-protein coding RNA (approximately 22 nucleotides) molecules that regulate gene expression; generally at the post-transcriptional level. Such RNAs may contribute to cancer formation and progression by regulating the expression of c-oncogenes and tumor suppressor genes or by acting as oncogenes or tumor suppressor genes. Recent evidence suggests that specific miRNAs, as well as mRNAs, may have a role as extracellular biomarkers. In this investigation, miRNAs and mRNAs are being investigated as potential biomarkers for both predicting response to the new therapies as well as monitoring the effectiveness of response. RESEARCH OBJECTIVES

1. To evaluate ADAM10 and ADAM17 as potential therapeutic targets for the treatment of triple- 2. To evaluate c-Met as a potential therapeutic targets for the treatment of triple-negative breast 3. To evaluate miRNAs and mRNAs as biomarkers for predicting and monitoring response to these RESEARCH TEAM
ADAMs Group

Dr Patricia McGowan, Post-doctoral Fellow Dr Aisling Pierce*, Post-Doctoral Fellow c-Met Group
miRNA/mRNA Group
*These investigators are not directly funded from the MTCI grant RECENT PUBLICATIONS / KEY OUTPUTS

1. Duffy MJ, O'Donovan N, Crown J. Use of molecular markers for predicting therapy response in cancer patients. Cancer Treat Rev. 2010 Aug 2. [Epub ahead of print] 2. Browne BC, Crown J, Venkatesan N, Duffy MJ, Clynes M, Slamon D, O'Donovan N. Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Ann Oncol. 2010 Jul 20. [Epub ahead of print] 3. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 2010;9:1489-502. Epub 2010 May 25. 4. Walsh S, Tryfonopoulos D, Quinn C, Flanagan L, Pierce A, McDermott E, Evoy D, O’Donovan N, Crown J, Duffy MJ. c-Src: A Potential Target for the Treatment of Triple-Negative Breast Cancer. J Clin Oncol 2010;28:7s, (suppl; abst 10617) 5. Friel AM, Corcoran C, Crown J, O'Driscoll L. Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer. Breast Cancer Res Treat. 2010 Jun 15. [Epub ahead 6. Germano S, Rani S, Kennedy S, Crown J, Clynes M, O’Driscoll L (2010). Melanoma-associated antigen family protein-D4: clinical significance and funcational relevance in breast cancer. Breast Cancer Res. 12; S10-11 (suppl 1; abstract 32) 7. Friel AM, Crown J, O’Driscoll L (2010). Analysis of gene expression as relevant to cancer cells and circulating tumour cells In: Gene Expression Profiling; Methods in Molecular Biology (in


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