• Role of PXR in drug metabolism of TNBC and its cross talk with other important drug-metabolism related molecules
  • Vida Akhgari,1 Flora Forouzesh,2 Mohammad Amin Javidi,3,*
    1. Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
    2. Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
    3. Department of Integrative Oncology, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.


  • Introduction: Breast cancer consists different molecular subtypes based on the expression of cell surface receptors (ER, PR, and HER-2), and Ki-67 level, as well as their prognosis. Accordingly, there 5 different subtypes (Luminal A, Luminal B, HER-2 enriched, Triple negative/basal-like, and normal- like). Management and prognosis of each subtypes differ, somehow, mainly due to the new treatment strategies e.g., targeted/endocrine therapy(1). Utilizing the most efficient dose of chemotherapy drugs would result in the highest efficiency with the least side effect. In this regard, Pharmacokinetics, and pharmacodynamics play crucial role in precision medicine of these patients who receive, chemotherapy. Pharmacokinetics deals with the amount required of a drug to reach the target site in the body, while pharmacodynamics deals with how receptors, ion channels and enzymes respond to different drugs(3).
  • Methods: In this article, the keywords of breast cancer, PXR, TNBC, drug metabolism are used in databases : Pubmed, Google Scholar, Scopus, ScienceDirect, ResearchGate.
  • Results: Pregnane X Receptor role in cancer and drug metabolism Pregnane X receptor (PXR) is a nuclear receptor that plays a significant role in chemotherapy outcomes by influencing the metabolism, drug resistance, tumor sensitivity, apoptosis, and pharmacokinetic parameters of various chemotherapeutic agents in both cancer cell lines and patients(5). Recent studies have highlighted the significance of PXR expression in tumor tissues of patients with TNBC, linking it to patient prognosis(2). The metabolic process mediated by PXR occurs in three phases: Phase I: Involves the action of metabolizing enzymes that introduce functional groups into xenobiotics. Phase II: Involves conjugating enzymes that facilitate the attachment of polar groups to metabolites, enhancing their solubility and excretion. Phase III: Involves transporters that facilitate the efflux of metabolites and drugs from cells (2) (figure 1). PXR Mechanism of Action and molecular cross-talks Upon ligand binding, PXR undergoes a conformational change that activates its signaling pathway. This activation leads to the translocation of PXR from the cytoplasm to the nucleus, where it forms a heterodimer with retinoid X receptor (RXR). This complex then binds to specific response elements in the promoter regions of target genes, regulating their transcription (2). Transcription factor E26 transformation-specific sequence 1 (ETS-1) and N-α-acetyltransferase 10 (NAA10) have been shown to interact with the PXR promoter, enhancing the activation of downstream genes associated with drug resistance. CYP3A4 plays a significant role in substrate oxidation and pharmacokinetic drug-drug interactions, leading to decreased plasma concentrations and reduced therapeutic efficacy of anticancer drugs. Therefore, treatment with PXR antagonists, which inhibit CYP3A4 at the transcriptional level, may enhance the therapeutic effects of these drugs(4). According to a study FBI-1 is a factor that binds to the inducer of short transcripts-1, enhancing the resistance of TNBC cells to chemotherapeutic agents by repressing the expression of microRNA-30c, which targets the PXR. MicroRNA-30c reduces PXR expression by interacting with the 3′-UTR of PXR, whereas FBI-1 increases PXR expression by inhibiting miR-30c. This research demonstrates that the miR-30c/PXR axis is modulated by FBI-1 in TNBC drug resistance, suggesting potential new strategies for the treatment of this aggressive cancer type(6). PXR appears to have dual roles in the development of resistance to chemotherapeutic agents.For instance, following treatment with a PXR agonist, an inactive anticancer prodrug may be metabolized more extensively into an active metabolite, potentially enhancing its anticancer efficacy. Conversely, the activation of PXR may increase the metabolism of active drug forms into less active metabolites or facilitate their excretion, leading to an overall increase in resistance to chemotherapy (7). Given the extensive diversity of compounds that activate PXR and its role in coordinating various biological processes, it is reasonable to expect interactions between PXR and other nuclear receptors, such as FXR, CAR, PPARα, LXR, and androgen receptor. These interactions may facilitate more effective regulation of cellular responses to different compounds and enhance the coordination of metabolic processes. In essence, PXR and these receptors may work synergistically to enable cells to adapt to environmental and metabolic changes(8). The constitutive androstane receptor (CAR), similar to PXR, is a nuclear receptor recognized for its role in xenobiotic detoxification through the regulation of drug metabolism enzymes and transporters. The structure of CAR includes a N-terminal domain (NTD), a ligand-binding domain (LBD), a hinge region (H), and a DNA-binding domain (DBD). The nuclear translocation of CAR can be facilitated by ligand binding as well as post-translational modifications (9) After xenobiotics enter the cell, they trigger the cytoplasmic-nuclear translocation of CAR by promoting the release of currently unidentified proteins. Subsequently, CAR heterodimerizes with RXR, binds to their respective response elements, and enhances the transcription of target genes (10).
  • Conclusion: Understanding the intricate relationship between PXR signaling, drug metabolism, and cancer progression is essential for developing more effective treatment strategies. Targeting PXR and other receptors involved in the metabolism of chemotherapy drugs in particular TNBC could potentially enhance the efficacy of existing therapies and mitigate the challenges associated with drug resistance in advanced metastatic Breast cancer.
  • Keywords: TNBC_Breast Cancer _ PXR _ Drug Metabolism