Functional pathways analyses to identify candidate therapeutic targets in triple-negative breast cancer

Abstract

569 Background: In the present study, we have analyzed dysregulated pathways in triple-negative breast cancers. Methods: Two datasets of cDNA arrays were used to identify differentially expressed genes between triple negative breast cancer and either normal/benign breast tissue or other molecular classes. The first dataset (I) was included 165 samples. The second data set (II) included 148 samples. Pathway analyses (gene set) were done based using BRB array tool and a software developed in house (SBIME). Results: Fifteen and 27 patients presented a triple negative breast cancer in the dataset I and II respectively. Ten and eleven pathways were significantly different between triple negative and other molecular classes in dataset I and II respectively (LS permutation p value<0.01). Six pathways were common between the two datasets (p53, cyclin E, E2F1, p27 phosphorylation, Ran, cycle regulation). We then focused the analyses on differential pathways between triple negative and normal/benign tissue. In the dataset I, targetable pathways were identified (hotelling t-test <10–7) including VEGF signalling pathway, proteasome, Hedgehog and Notch pathway. In addition, an enrichment of histone overexpression was observed in triple negative breast cancer (3% of overexpressed genes, ratio expression >2). In the dataset II, histone (p = 2x10–6), chromosome organization (p = 2x10–4) gene sets were enriched in triple negative breast cancer. We then assessed whether such pathway dysregulations could be linked to genomic aberration enriched in triple negative breast cancer. Using high resolution CGH arrays (Agilent, 4*44K) on 53 triple negative breast cancers, we detected that 31% of triple negative tumors presented a gene gain in 6p21 and 6p22, two regions that contain VEGFA gene (6p21) and a cluster of histones (6p22). Conclusions: Triple negative breast cancers present dysregulation of targetable pathways, including VEGF signaling and chromosome organization. Dysregulation of these two pathways could be related to gene gains in 6p21–22 regions observed in 30% of triple negative breast cancer. No significant financial relationships to disclose.