Phorbol Ester TPA Modulates Chemoresistance in the Drug Sensitive Breast Cancer Cell Line MCF-7 by Inducing Expression of Drug Efflux Transporter ABCG2

Recent studies have indicated a link between levels of cyclooxygenase-2 (COX-2) and development of themultidrug resistance (MDR) phenotype. The ATP-binding cassette sub-family G member 2 (ABCG2) is a majorMDR-related transporter protein that is frequently overexpressed in cancer patients. In this study, we aimedto evaluate any positive correlation between COX-2 and ABCG2 gene expression using the COX-2 inducer12-O-tetradecanoylphorbol-13-acetate (TPA) in human breast cancer cell lines. ABCG2 mRNA and proteinexpression was studied using real-time RT-PCR and flow cytometry, respectively. A significant increase ofCOX-2 mRNA expression (up to 11-fold by 4 h) was induced by TPA in MDA-MB-231 cells, this induction effectbeing lower in MCF-7 cells. TPA caused a considerable increase up to 9-fold in ABCG2 mRNA expression inparental MCF-7 cells, while it caused a small enhancement in ABCG2 expression up to 67 % by 4 h followedby a time-dependent decrease in ABCG2 mRNA expression in MDA-MB-231 cells. TPA treatment resultedin a slight increase of ABCG2 protein expression in MCF-7 cells, while a time-dependent decrease in ABCG2protein expression was occurred in MDA-MB-231 cells. In conclusion, based on the observed effects of TPA inMDA-Mb-231 cells, it is proposed that TPA up-regulates ABCG2 expression in the drug sensitive MCF-7 breastcancer cell line through COX-2 unrelated pathways.