Progesterone Receptor Down-Regulates BCRP Expression via Binding to the Progesterone Response Element in Breast Cancer.
Cancer Sci. 2012 Feb 20. Epub 2012 Feb 20. PMID: 22348324
Department of Pathology, School of Medicine, Shandong Univeristy, Shandong, China.
Breast cancer resistance protein (BCRP) plays a major role in multidrug resistance (MDR). Sequence analysis reveals there is a novel progesterone response element (PRE) in the BCRP promoter, suggesting progesterone receptor (PR) may have a function in the regulation of BCRP expression. We examined the expressions of BCRP, PR, ERα, AR and Her-2 in 95 breast cancer samples by immunohistochemistry. Then, to identify the role of PR in the regulation of BCRP expression, two constructs encoding full length BCRP cDNA driven by putative PRE promoter or constitutive CMV promoter were transfected into MCF-7 and MDA-MB-231, respectively. RT-PCR and Western blotting were used to detect the expression of BCRP. Further electrophoretic mobility shift assay (EMSA) was utilized to verify the nuclear protein-DNA specific binding. We innovatively found that the expression of BCRP negatively related with that of PR and ERα in breast cancer by immunohistochemistry. While in cellular level, after treated by progesterone and 17β-estradiol, BCRP mRNA and protein levels were significantly reduced in a concentration-dependent manner in MCF-7/P-BCRP cells with PR bound to the identified PRE in BCRP promoter. Our results demonstrated that active PR inactived BCRP expression via progesterone-PR complexes binding to PRE in BCRP promoter in breast cancer cells. © 2012 Japanese Cancer Association.