Progesterone negatively regulates BCRP in progesterone receptor-positive human breast cancer cells.

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.