Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Abstract

The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan-Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients' clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan-Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.

A Supervised Network Analysis on Gene Expression Profiles of Breast Tumors Predicts a 41-Gene Prognostic Signature of the Transcription FactorMYBacross Molecular Subtypes

“…Our finding shows that ARNT2 is not a prognostic indicator in both 90A cohort and 181A cohort (III and IV of Figure S5.2). However, its mRNA expression is up-regulated in tumor component, which is consistent with the report [20]. Liu et al [21] reported that ARNT2 dimerizes with SIM1 to up-regulate their downstream target genes (268 probes) in vitro , which are predicted to be functional in seven categories—transcription regulators, signaling components, metabolic enzymes, channels and transporters, cell adhesion and migration, miscellaneous and uncharacterized.…”

“…Qin et al [19] reported ARNT2 affecting HIF1 regulatory signaling and metabolism in human breast cancer cell model. It is a potential favorable prognostic factor in breast cancer when it is elevated and it is expressed higher in tumor component than in non-tumor component [20]. Our finding shows that ARNT2 is not a prognostic indicator in both 90A cohort and 181A cohort (III and IV of Figure S5.2).…”

Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells

“…Extensive evidences have clearly indicated the modulatory role of the ligand-activated Ahr in different types of cancers [26–28]. In breast cancer, previous studies have demonstrated that the agonist-activated Ahr modulates invasiveness and metastasis of breast cancer cells, the main causes for tumor recurrence, suggesting Ahr as a promising therapeutic strategy [29, 17, 14, 16].…”

Modulation of the pentose phosphate pathway alters phase I metabolism of testosterone and dextromethorphan in HepG2 cells

“…Therefore, the metabolism of a drug in cancer cells is of great interest for scientists interested in designing anti-tumor drugs and PK-PD study. Previous studies have shown that the expression levels of many CYP450 isoforms and UDPglucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), sulfotransferase (SULTs) and sulfatase (SULFs) in hepatoma carcinoma, breast cancer and lung cancer tissues were different from their corresponding normal tissues [17,[35][36][37] . The intracellular NADPH levels [38][39][40] were also different in cancer samples.…”