Interplay between the Nuclear Receptor Pregnane X Receptor and the Uptake Transporter Organic Anion Transporter Polypeptide 1A2 Selectively Enhances Estrogen Effects in Breast Cancer

2008/11/14 by Henriette E. Meyer zu Schwabedissen, Rommel G. Tirona, Cindy S. Yip +3 · 134 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Pharmacology, Toxicology and Pharmaceutics · #ATP-binding cassette transporter #Biochemistry #Biology #Breast cancer #Cancer #Cancer research #Chromatin immunoprecipitation #Drug Transport and Resistance Mechanisms #Estrogen and related hormone effects #Estrogen receptor #Gene #Gene expression #Genetics #Multidrug resistance-associated protein 2 #Nuclear receptor #Organic anion transporter 1 #Organic anion-transporting polypeptide #Pharmacogenetics and Drug Metabolism #Pharmacology #Pregnane X receptor #Promoter #Solute carrier family #Transcription factor #Transporter

paper · pdf · doi:10.1158/0008-5472.can-08-0265

published in Cancer Research 68(22), 9338-9347 (American Association for Cancer Research)

openalex publication_date 2008/11/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

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.

Citations

• Intestinal Drug Transporter Expression and the Impact of Grapefruit Juice in Humans

Cited by

• St. John’s Wort Formulations Induce Rat CYP3A23-3A1 Independent of Their Hyperforin Content
• Hyperforin-Induced Activation of the Pregnane X Receptor Is Influenced by the Organic Anion-Transporting Polypeptide 2B1
• The 5′-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2
• Organic anion transporting polypeptides: Pharmacology, toxicology, structure, and transport mechanisms
• The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer
• The Regulation of Steroid Action by Sulfation and Desulfation
• Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells. [europepmc]
• Pharmacogenetics of the organic anion transporting polypeptide 1A2. [europepmc]
• Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists. [europepmc]
• Xenobiotic, bile acid, and cholesterol transporters: function and regulation. [europepmc]
• Nuclear receptor-mediated regulation of carboxylesterase expression and activity. [europepmc]
• Orphan nuclear receptors as targets for drug development. [europepmc]
• Environmental and genetic factors affecting transport of imatinib by OATP1A2. [europepmc]
• The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. [europepmc]
• Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. [europepmc]
• Role of CAR and PXR in xenobiotic sensing and metabolism. [europepmc]
• Compartment-specific gene regulation of the CAR inducer efavirenz in vivo. [europepmc]
• Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response. [europepmc]
• Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. [europepmc]
• The SLCO (former SLC21) superfamily of transporters. [europepmc]
• Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy. [europepmc]
• Pregnane X Receptor and Cancer: Context-Specificity is Key. [europepmc]
• The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers. [europepmc]
• Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development. [europepmc]
• Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology. [europepmc]
• Clinical relevance of St. John's wort drug interactions revisited. [europepmc]
• Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug-Drug Interaction Studies. [europepmc]
• Solute transporters and malignancy: establishing the role of uptake transporters in breast cancer and breast cancer metastasis. [europepmc]
• Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion-transporting polypeptides. [europepmc]
• Transcriptional Regulation of Solute Carrier (SLC) Drug Transporters . [europepmc]
• The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy. [europepmc]

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