Abstract P2-09-23: Investigating VAV3 Expression as a Novel Biomarker and Indicator of Chemosensitivity in Basal-Like Breast Cancer

Abstract

Abstract Background: Basal-like breast (BLB) cancer accounts for ∼15% of all breast cancers diagnosed. Patients with BLB cancer are typically younger, present with higher tumor grade and despite recent advances in therapy, still have a poor outcome. BLB cancers are the most proliferative breast tumor sub-type, are commonly triple-negative (ER-, PgR-, HER2/neu-), and often harbor mutations in TP53 and BRCA1. The biological drivers of disease progression in this tumor subtype remains poorly understood. Recently, VAV3, a guanine nucleotide exchange factor and a member of the of the Rho/Rac/Cdc42 GTPase superfamily, has been reported as overexpressed and oncogenic in ER+ breast cancer cells. Our preliminary studies using publicly available microarray data indicates a consistent lack of VAV3 in BLB cancer, particularly those patients with shorter survival time following chemotherapy. We therefore hypothesize that VAV3 is a novel biomarker of BLB cancer and potential predictor of chemosensitivity in this subtype. Materials and Methods: Gene expression microarray technology, qRTPCR and western blotting was used to investigate relative expression of VAV3 in a panel of breast cancer cell lines and tumors. Array Comparative Genomic Hybridization and Fluorescence in Situ Hybridization were used to evaluate VAV3 gene copy number. BLB cancer cell lines stably overexpressing VAV3 were developed to evaluate the role of VAV3 in sensitivity to chemotherapy. Results: Unsupervised hierarchical clustering revealed low VAV3 expression in BLB tumors compared to all other intrinsic subtypes. Consistently lower VAV3 mRNA and protein expression were observed in BLB cancer cell lines compared to luminal epithelial cell lines, consistent with our in silico observations. We confirmed that low VAV3 expression in the BLB cancer cell lines is not due to gene copy number loss. Ectopic expression of VAV3 in MDA-MB-231 BLB cancer cells significantly enhanced their sensitivity to cisplatin. Discussion: A consistent lack of VAV3 gene expression is evident in BLB tumors, however the mechanism underlying this loss is yet to be elucidated. Our findings support a hypothesis that low VAV3 expression is a potential diagnostic biomarker of BLB cancer, and that VAV3 expression may be a predictor of response to chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-23.