Transcription factor-mediated regulation of the BCRP/ABCG2 efflux transporter: a review across tissues and species

ABSTRACT

Introduction: The breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette superfamily of transporters. Using the energy garnered from the hydrolysis of ATP, BCRP actively removes drugs and endogenous molecules from the cell. With broad expression across the liver, kidney, brain, placenta, testes, and small intestines, BCRP can impact the pharmacokinetics and pharmacodynamics of xenobiotics.

Areas covered: The purpose of this review is to summarize the transcriptional signaling pathways that regulate BCRP expression across various tissues and mammalian species. We will cover the endobiotic- and xenobiotic-activated transcription factors that regulate the expression and activity of BCRP. These include the estrogen receptor, progesterone receptor, peroxisome proliferator-activated receptor, constitutive androstane receptor, pregnane X receptor, nuclear factor e2-related factor 2, and aryl hydrocarbon receptor.

Expert opinion: Key transcription factors regulate BCRP expression and function in response to hormones and xenobiotics. Understanding this regulation provides an opportunity to improve pharmacotherapeutic outcomes by enhancing the efficacy and reducing the toxicity of drugs that are substrates of this efflux transporter.

KEYWORDS:

• ABCG2
• Breast Cancer Resistance Protein (BCRP)
• transcription
• transporter

Article highlights

• The breast cancer resistance protein (ABCG2/BCRP) is an ATP-dependent efflux transporter responsible for limiting the cellular accumulation of a wide variety of antibiotics, chemotherapeutics, anti-diabetics, anti-hypertensives, environmental contaminants, and endogenous molecules.

• BCRP maintains cellular homeostasis by actively eliminating endogenous intracellular substrates. Disruption of BCRP expression and/or function has been associated with pathophysiology including gout.

• Drug transporter expression and function is regulated by nuclear hormone receptors and xenobiotic-activated transcription factors. Steroid receptors (ER, PR), xenobiotic receptors (CAR, PXR, PPAR), and transcription factors (AHR, NRF2) are all involved in the coordinated regulation of BCRP expression.

• While BCRP/Bcrp regulation by endobiotic- and xenobiotic-activated transcription factors is largely similar across mammalian species, there are notable exceptions that are important in translating studies from experimental models to humans.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Institutes of Health – National Institute of Environmental Health Sciences [grant numbers T32ES007148, R01ES029275, R01ES021800, R01GM123330, F31ES029794, and P30ES005022]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.