Breast Tumors with Elevated Expression of 1q Candidate Genes Confer Poor Clinical Outcome and Sensitivity to Ras/PI3K Inhibition

Abstract

Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA–drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors.

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

“…EXO1 has been associated with different types of cancers owning to its mutations, including colon, breast, ovarian, lung, pancreatic, and gastric tract cancer (Bau et al, ; Hansen et al, ; Jin et al, ; Sun, Zheng, & Shen, ). Nevertheless, the overexpression of EXO1 has also been reported in several other cancers associated with poor prognosis, which in part is related to increased DNA repair activity (Axelsen, Lotem, Sachs, & Domany, ; Dai et al, ; de Sousa et al, ; Muthuswami et al, ). In this study, AURKA, CCNB1, CCNF, and EXO1 were significantly upregulated in CRC compared with normal samples, and in CRC patients, the survival rate was positively correlated with the high expression of these genes.…”

A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles

“…Examples of CMap use include the anthelmintic drug parbendazole as an inducer of osteoclast differentiation (Brum et al, 2015), celastrol as a leptin sensitizer (Liu et al, 2015), compounds targeting COX2 and ADRA2A as potential diabetes treatments (Zhang et al, 2015), small molecules that mitigate skeletal muscular atrophy (Dyle et al, 2014) and spinal muscular atrophy (Farooq et al, 2009), and new therapeutic hypotheses for the treatment of inflammatory bowel disease (Dudley et al, 2011) and cancer (Singh et al, 2016); (Muthuswami et al, 2013; Wang et al, 2008); (Schnell et al, 2015); (Fortney et al, 2015; Wang et al, 2011); (Churchman et al, 2015); (Rosenbluth et al, 2008); (Saito et al, 2009); (Stockwell et al, 2012). …”

A Next Generation Connectivity Map: L1000 Platform And The First 1,000,000 Profiles

“…Recently published uses of the CMap pilot dataset include discovery of the anthelmintic drug parbendazole as an inducer of osteoclast differentiation (Brum et al, 2015), the triterpene celastrol as a leptin sensitizer (Liu et al, 2015), compounds targeting COX2 and ADRA2A as potential diabetes treatments (Zhang et al, 2015), small molecule therapeutics for skeletal muscular atrophy (Dyle et al, 2014) and spinal muscular atrophy (Farooq et al, 2009), and new therapeutic hypotheses for the treatment of inflammatory bowel disease (Dudley et al, 2011) and cancer (Singh et al, 2016); (Muthuswami et al, 2013;Wang et al, 2008); (Schnell et al, 2015); (Fortney et al, 2015;Wang et al, 2011); (Vilar et al, 2009); (Churchman et al, 2015).…”