BACKGROUND/AIMS: Breast cancer resistance protein (BCRP) plays a crucial role in multidrug resistance (MDR). Previous studies have shown that steroid hormones, like progesterone (PROG), regulate BCRP expression. The presence of a progesterone response element (PRE) in the BCRP promoter, suggests that PROG may regulate transcription of BCRP. METHODS: To investigate the role of PROG in the regulation of BCRP expression, two constructs encoding full-length BCRP driven by either an endogenous PRE promoter or a constitutive CMV promoter, were transfected into T47D cells that express the progesterone receptor (PR) or into PR-negative MDA-MB-231 cells. RESULTS: After treatment with PROG, qPCR and Western blotting analyses indicated that BCRP mRNA and BCRP protein levels were significantly reduced in a dose-dependent manner in PR-positive cells, but PROG had no significant effect on BCRP levels in the PR-negative cells. The effect observed in PR-positive cells was reversed by co-treatment with RU-486, a specific PROG inhibitor. Cytometric analysis confirmed that BCRP-mediated drug efflux was inhibited and chemosensitivity to mitoxantrone was markedly increased by PROG treatment. CONCLUSION: These results suggest that PROG reverses BCRP-mediated MDR by down-regulating BCRP expression in breast cancer cells by affecting transcription from the PRE-containing BCRP promoter. Our studies suggest that breast cancer patients with BCRP-mediated MDR may be successfully treated with PROG.
BACKGROUND/AIMS: Breast cancer resistance protein (BCRP) plays a crucial role in multidrug resistance (MDR). Previous studies have shown that steroid hormones, like progesterone (PROG), regulate BCRP expression. The presence of a progesterone response element (PRE) in the BCRP promoter, suggests that PROG may regulate transcription of BCRP. METHODS: To investigate the role of PROG in the regulation of BCRP expression, two constructs encoding full-length BCRP driven by either an endogenous PRE promoter or a constitutive CMV promoter, were transfected into T47D cells that express the progesterone receptor (PR) or into PR-negative MDA-MB-231 cells. RESULTS: After treatment with PROG, qPCR and Western blotting analyses indicated that BCRP mRNA and BCRP protein levels were significantly reduced in a dose-dependent manner in PR-positive cells, but PROG had no significant effect on BCRP levels in the PR-negative cells. The effect observed in PR-positive cells was reversed by co-treatment with RU-486, a specific PROG inhibitor. Cytometric analysis confirmed that BCRP-mediated drug efflux was inhibited and chemosensitivity to mitoxantrone was markedly increased by PROG treatment. CONCLUSION: These results suggest that PROG reverses BCRP-mediated MDR by down-regulating BCRP expression in breast cancer cells by affecting transcription from the PRE-containing BCRP promoter. Our studies suggest that breast cancerpatients with BCRP-mediated MDR may be successfully treated with PROG.