The
ligand-activated
nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of
drug metabolizing
enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in
breast cancer. However, the relevant pathway or target genes of PXR in
breast cancer biology and progression have not yet been fully clarified. In this study, we show that
mRNA expression of
organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of
estrogen metabolites, is nearly 10-fold greater in
breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in
breast cancer tissue. Interestingly, treatment of
breast cancer cells in vitro with the PXR agonist
rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a
hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of
estrone 3-sulfate. The
rifampin response was abrogated after
small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located approximately 5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using
chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the
rifampin effect on the cellular uptake of E(1)S. These data provide important new insights into the interplay between a
xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of
breast cancer and may also prove to be heretofore unrecognized targets for
breast cancer treatment.