Regulation of the apoptotic genes in breast cancer cells by the transcription factor CTCF

Abstract

not available at time of publication. L2 Biomarkers for the diagnosis and prediction of therapeutic response in clinical breast cancer Abstract not available at time of publication. L3 Recent advances in treatment of metastatic breast cancer R Coleman Abstract not available at time of publication. SPEAKER PRESENTATIONS O1 Male versus female breast cancer: a comparative study of 523 matched cases reveals diff erences behind similarity V Speirs 1 , G Ball 2 , Male Breast Cancer Consortium Retrospective studies on male breast cancer (MBC) have suff ered from small numbers of cases available from any one centre; thus a signifi cant problem in eff ectively studying this disease is accruing suffi ciently large numbers to allow comparative analysis of biomarkers associated with response. Using a coordinated multicentre approach, we present the fi rst large-scale study to address the relevance of the expression of hormone receptors in MBC and female breast cancer (FBC) using immunohistochemistry combined with a novel bioinformatics approach. Following ethical approval, 523 archival blocks (260 MBCs and 263 matched FBCs) were obtained retrospectively. Tissue microarrays were constructed and sections stained for ERα, ERβ1, ERβ2, ERβ5, total PR, PRA, PRB and AR and typed using CK5/6, CK14, CK18 and CK19 by immunohistochemistry. Following scoring, a range of ordination techniques were conducted on the datasets including hierarchical clustering and principal component analysis (PCA) to determine the diff erential nature of infl uences and interactions between MBC and FBC. Luminal A subgroup (ERα + and/or PR + , HER2-) was the most common phenotype in both sexes. Luminal B (ERα + and/or PR + , HER2 +) was not seen in males, while basal-like tumours (ERα-, PR-, HER2-, CK5/6 +) were infrequent in both. Hierarchical clustering revealed common clusters between MBC and FBC including total PR-PRA-PRB and ERβ1/2 clusters. ERα occurred on distinct clusters between males and females. AR, ERβ1, ERβ2 and ERβ5 all existed on the same cluster but with a diff erent substructure, particularly around the positioning of AR. ERα associated with this cluster in the male but not the female group. PCA confi rmed that in both groups strong infl uences came from PR-PRA-PRB. In MBC strong infl uences additionally came from AR and ERβ1, ERβ2 and ERβ5, whereas in FBC strong infl uences came from ERα alone. Our data support the hypothesis that breast cancer is biologically diff erent in male and females, which could have implications for therapy. O2 Upregulation of ADAM proteases and HER ligands through a feedback loop mediates acquired resistance to trastuzumab in HER2-amplifi ed breast cancer Introduction The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. It is still poorly understood how Herceptin exerts its mechanism of action and how the acquired resistance to this drug occurs. Materials and methods We used a multidisciplinary approach including fl uorescence resonance energy transfer and biochemical methods to assess the eff ects of Herceptin on various signalling pathways and to determine the acquired resistance mechanisms of Herceptin in various HER2-positive breast cell lines and a BT474 xenograft model. Results We have shown that Herceptin does not decrease HER2 phosphorylation despite the eff ect on HER2 receptor downregulation. HER2 phosphorylation is maintained by the activation of EGFR, HER3 and HER4 via their dimerisation with HER2 in breast cancer cells. The activation of EGFR, HER3 and HER4 is induced by HER ligand release, including heregulin and betacellulin. The release of HER ligands is mediated by ADAM proteases including ADAM17/TACE. Furthermore, we demonstrated that the feedback loop involving HER ligands and ADAM proteases is activated due to a decrease in PKB phosphorylation induced by Herceptin treatment. The feedback loop is also switched on when PKB phosphorylation is decreased by a PKB inhibitor. We have shown that the feedback loop activates the HER receptors and maintains HER2 phosphorylation in response to Herceptin. Herceptin in combination with a panHER inhibitor also caused a much greater tumour inhibition compared with Herceptin or panHER inhibitor alone in the xenograft model. Conclusions Our data provide evidence that Herceptin as monotherapy may result in poor outcome for patients due to the escape mechanisms through a feedback loop involving the upregulation of ADAM proteases and HER ligands. We have provided a novel mechanism of acquired resistance to Herceptin in HER2-positive breast cancer and have resolved the inconsistencies in the literature regarding the eff ect of Herceptin on HER2 phosphorylation.