title: Progesterone receptor downregulates breast cancer resistance protein expression via binding to the progesterone response element in breast cancer.
abstract: 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, estrogen receptor α (ERα), androgen receptor (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. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the expression of BCRP. Further electrophoretic mobility shift assay (EMSA) was used 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 at a cellular level, after being 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.
authors.affiliation: Department of Pathology, School of Medicine, Shandong Univeristy, Shandong, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Su
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Gengyin
authors.initials: G
authors.lastname: Zhou
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D011374:Progesterone / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D011374:Progesterone