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 a (ERa), 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 ERa in breast cancer by immunohistochemistry. While at a cellular level, after being treated by progesterone and 17b-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. (Cancer Sci 2012; 103: 959-967) T o date, breast cancer is the most prevalent type of malignant tumor in women, and the multidrug resistance (MDR) is a major obstacle in successful chemotherapy. Breast cancer resistance protein (BCRP) is identified first from drug selected human breast cancer cells (MCF-7/AdrVp).(1) It overexpresses in many cancer cell lines and belongs to the subfamily of G of the ATP-binding cassette (ABC) transporter superfamily.(2-4) It can efflux a variety of chemotheraputic agents including mitoxantrone, topotecan and anthracyclines out of the cell.(5) Therefore, the investigation of mechanism of BCRP expression may bring out better treatment measures for cancer therapy.Recent reports suggest that the BCRP expression may be adjusted at the promoter level by steroid hormones, such as estrogen, progesterone and testosterone via classical pathways, but the data have some conflicts. (6)(7)(8) Hormone-receptor (HR) status has a major role in the prognosis and treatment of breast cancer patients. Estrogen plays an important role in the regulation of progesterone receptor (PR) in both mammary gland and breast cancer. However, there are still 2.00-8.12% of breast cancer patients immunohistochemically with ER-/PR+ and it often occurs in young or middle-aged women. The ER-/PR+ tumors are larger in size and appear more aggressive compared with the group of ER+/ PR+.(9) Therefore, in those ER negative breast cancer cells, the PR expression level should be greatly compromised, which implies that the role of PR remains an enigma.Our group has firstly revealed that toremifen can ...