Dataset Information

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.

SUBMITTER: Muthuswami M

PROVIDER: S-EPMC3798322 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Breast tumors with elevated expression of 1q candidate genes confer poor clinical outcome and sensitivity to Ras/PI3K inhibition.

Muthuswami Muthulakshmi M Ramesh Vignesh V Banerjee Saikat S Viveka Thangaraj Soundara S Periasamy Jayaprakash J Bhaskar Rao Divya D Barnabas Georgina D GD Raghavan Swetha S Ganesan Kumaresan K

PloS one 20131017 10

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 ...[more]

PMID: 24147022

Similar Datasets

Project description:The 52-kDa FK506-binding protein (FKBP52), a regulator of steroid hormone receptor signaling, is potentially involved in a variety of hormone-dependent cancer types. The present study investigated the expression and clinical implications of FKBP52 in breast cancer. Immunohistochemistry was performed on samples from 145 breast cancer patients and on 66 unmatched breast non-cancerous tissues (as controls) to determine the expression level of FKBP52. Publicly available microarray and RNA-seq datasets used in the present study were downloaded from the European Bioinformatics Institute ArrayExpress. Kaplan-Meier survival analysis was also performed. FKBP52 expression was moderately higher in the tumors than that in the non-cancerous tissues, but this difference was not statistically significant (P=0.176). However, available microarray datasets exhibited a significant difference in FKBP52 mRNA levels between breast tumors and controls. In the 145 breast cancer patients, elevated FKBP52 expression was significantly associated with advanced Tumor-Node-Metastasis (TNM) stage (P=0.015), lymph node metastasis (P=0.015) and tumors with poor histological differentiation (P=0.047). FKBP52 expression was negatively associated with estrogen receptor expression (P=0.033), but positively associated with human epidermal growth factor receptor 2 expression (P=0.033). However, there was no association between FKBP52 and progesterone receptor expression. Survival analyses demonstrated that FKBP52 was indicative of a poor overall survival rate (P=0.026), which was consistent with the result of Kaplan-Meier analysis, exhibiting a negative association between the mRNA of FKBP52 and overall survival (OS) (P=0.044). Other than for FKBP52 [hazard ratio (HR), 2.315; 95% confidence interval (CI), 1.077-4.975; P=0.032], univariate analysis revealed that clinical stage exhibited a significant influence on the prognosis of the breast cancer patients (HR, 2.148; 95% CI, 1.011-4.566; P=0.047). However, multivariate analysis revealed that only clinical stage, not FKBP52, was an independent prognostic factor (HR, 2.721; 95% CI, 1.169-6.335; P=0.020). Patients were further classified according to their OS. Compared with the controls (3.94±2.992), FKBP52 expression in breast cancer patients with OS of ≤3 years (5.39±3.409; P=0.042) or OS of ≤5 years (5.88±3.473; P=0.005) was significantly increased, respectively. However, no significant difference in FKBP52 expression was observed between controls and individuals with an OS time of >3 years (4.84±3.769; P=0.109) or >5 years (5.32±3.372; P=0.090). Elevated FKBP52 expression may be involved in tumor progression and invasion, given its positive association with TNM stage and lymph node metastasis. Although it is not an independent predictor, FKBP52 has promise as a biological marker for estimating the progression of breast cancer.

Project description:Mast cells are the major effector cells in immunoglobulin E (IgE)-mediated allergy. The high affinity IgE receptor FcεRI, as well as G protein-coupled receptors (GPCRs) on the mast cell surface signals to phosphoinositide 3-kinase γ (PI3Kγ) to initiate degranulation, cytokine release, and chemotaxis. PI3Kγ is therefore considered as a target for treatment of allergic disorders. However, leukocyte PI3Kγ is key to many functions in innate and adaptive immunity, and attenuation of host defense mechanisms is an expected adverse effect that complicates treatment of chronic illnesses. PI3Kγ operates as a p110γ/p84 or p110γ/p101 complex, where p110γ/p84 requires Ras activation. Here we investigated if modulation of Ras-isoprenylation could target PI3Kγ activity to attenuate PI3Kγ-dependent mast cell responses without impairment of macrophage functions. In murine bone marrow-derived mast cells, GPCR stimulation triggers activation of N-Ras and H-Ras isoforms, which is followed by the phosphorylation of protein kinase B (PKB/Akt) relayed through PI3Kγ. Although K-Ras is normally not activated in Ras wild-type cells, it is able to compensate for genetically deleted N- and H-Ras isoforms. Inhibition of Ras isoprenylation with farnesyltransferase inhibitor FTI-277 leads to a significant reduction of mast cell degranulation, cytokine production, and migration. Complementation experiments expressing PI3Kγ adaptor proteins p84 or p101 demonstrated a differential sensitivity towards Ras-inhibition depending on PI3Kγ complex composition. Mast cell responses are exclusively p84-dependent and were effectively controlled by FTI-277. Similar results were obtained when GTP-Ras was inactivated by overexpression of the GAP-domain of Neurofibromin-1 (NF-1). Unlike mast cells, macrophages express p84 and p101 but are p101-dominated and thus remain functional under treatment with FTI-277. Our work demonstrates that p101 and p84 have distinct physiological roles, and that Ras dependence of PI3Kγ signaling differs between cell types. FTI-277 reduces GPCR-activated PI3Kγ responses in p84-expressing but not p101-containing bone marrow derived cells. However, prenylation inhibitors have pleiotropic effects beyond Ras and non-tolerable side-effects that disfavor further clinical validation. Statins are, however, clinically well-established drugs that have previously been proposed to block mast cell degranulation by interference with protein prenylation. We show here that Simvastatin inhibits mast cell degranulation, but that this does not occur via Ras-PI3Kγ pathway alterations.

Dataset Information

Breast tumors with elevated expression of 1q candidate genes confer poor clinical outcome and sensitivity to Ras/PI3K inhibition.

Publications

Breast tumors with elevated expression of 1q candidate genes confer poor clinical outcome and sensitivity to Ras/PI3K inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets