Abstract A184: Integrative molecular and functional profiling of HER2 amplified breast cancers to identify new gene targets.

Abstract

Abstract Up to 15% of all breast cancers are defined as HER2+ve where overexpression is due to amplification of the HER2 oncogene. Treatment of patients with these clinically aggressive tumors has been dramatically improved by the use of trastuzumab and lapatinib. However a significant proportion of patients' tumors remain resistant to these therapies. Therefore new biomarkers and additional therapeutic targets are urgently required for what remains a clinically challenging and biologically heterogeneous disease. We describe an integrated genetic, transcriptomic and functional analysis of a wide panel of genes amplified and overexpressed in HER2 amplified breast tumors to identify new gene targets. Molecular profiling of 45 sporadic primary HER2 amplified breast cancers, 14 commercially available HER2 amplified and 9 non HER2 amplified breast cancer cell lines was performed. Genome wide copy number and transcriptomic array data were integrated and identified 511 genes that were significantly overexpressed when amplified in the tumors. The functional significance of 369 of these genes, which were recurrently amplified in the cell lines, was examined using parallel high throughput siRNA screens. Multiple genetic dependencies were observed. We demonstrate that loss of cell viability following silencing of HER2 by multiple siRNAs significantly correlated with sensitivity to lapatinib and other HER2 targeted agents. We also show that silencing of TFAP2C caused significant loss of cell viability when amplified and overexpressed in multiple HER2 amplified breast cancer cell lines. Down regulation of HER2 expression and cell apoptosis was also observed. The potential clinical value of TFAP2C overexpression for patients with HER2+ve breast cancer is currently being explored in adjuvant HER2+ breast cancer trials of chemotherapy +/− HER2 targeted agents. We propose that TFAP2C amplification and overexpression represents a genetic dependency in HER2+ breast cancer and is a clinically relevant candidate biomarker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A184.