Interindividual Regulation of the Breast Cancer Resistance Protein/ ABCG2 Transporter in Term Human Placentas

Kristin M Bircsak; Jamie E Moscovitz; Xia Wen; Faith Archer; Poi Yu Sofia Yuen; Moiz Mohammed; Naureen Memon; Barry I Weinberger; Laura M Saba; Anna M Vetrano; Lauren M Aleksunes

doi:10.1124/dmd.117.079228

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Interindividual Regulation of the Breast Cancer Resistance Protein/ ABCG2 Transporter in Term Human Placentas

Journal article

Open access

Peer reviewed

Interindividual Regulation of the Breast Cancer Resistance Protein/ ABCG2 Transporter in Term Human Placentas

Kristin M Bircsak, Jamie E Moscovitz, Xia Wen, Faith Archer, Poi Yu Sofia Yuen, Moiz Mohammed, Naureen Memon, Barry I Weinberger, Laura M Saba, Anna M Vetrano, …

Drug metabolism and disposition, Vol.46(5), pp.619-627

05/2018

DOI: https://doi.org/10.1124/dmd.117.079228

PMCID: PMC5896368

PMID: 29386232

Abstract

European Continental Ancestry Group - genetics

Hispanic Americans - genetics

Humans

RNA, Messenger - genetics

ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics

Asian Continental Ancestry Group - genetics

African Americans - genetics

Genotype

Breast Neoplasms - metabolism

Placenta - metabolism

Pregnancy

Breast Neoplasms - genetics

Alleles

Polymorphism, Single Nucleotide - genetics

Adult

Female

Neoplasm Proteins - genetics

The breast cancer resistance protein (BCRP/ ) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. In this study, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex-branched DNA analysis. BCRP expression and genotypes were determined using Western blot and Fluidigm Biomark genetic analysis, respectively. Placentas were obtained from a racially and ethnically diverse population, including Caucasian (33%), African American (14%), Asian (14%), Hispanic (15%), and mixed (16%) backgrounds, as well as unknown origins (7%). Between placentas, BCRP mRNA and protein varied up to 47-fold and 14-fold, respectively. In particular, BCRP mRNA correlated significantly with known transcription factor mRNAs, including nuclear factor erythroid 2-related factor 2 and aryl hydrocarbon receptor. Somewhat surprisingly, single-nucleotide polymorphisms (SNPs) in the noncoding regions were not associated with variation in placental BCRP mRNA or protein. Instead, the coding region polymorphism (C421A/Q141K) corresponded with 40%-50% lower BCRP protein in 421C/A and 421A/A placentas compared with wild types (421C/C). Although BCRP protein and mRNA expression weakly correlated ( = 0.25, = 0.040), this relationship was absent in individuals expressing the C421A variant allele. Study results contribute to our understanding of the interindividual regulation of BCRP expression in term placentas and may help to identify infants at risk for increased fetal exposure to chemicals due to low expression of this efflux protein.

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Title: Interindividual Regulation of the Breast Cancer Resistance Protein/ ABCG2 Transporter in Term Human Placentas
Creators: Kristin M Bircsak - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Jamie E Moscovitz - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Xia Wen - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Faith Archer - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Poi Yu Sofia Yuen - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Moiz Mohammed - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Naureen Memon - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Barry I Weinberger - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Laura M Saba - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Anna M Vetrano - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)
Lauren M Aleksunes - Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children's Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.) aleksunes@eohsi.rutgers.edu
Publication Details: Drug metabolism and disposition, Vol.46(5), pp.619-627
Date published: 05/2018
Grant note: F31 HD082965 / NICHD NIH HHS R01 ES020522 / NIEHS NIH HHS T32 ES007148 / NIEHS NIH HHS P30 ES005022 / NIEHS NIH HHS U54 HD055764 / NICHD NIH HHS P50 HD055764 / NICHD NIH HHS
Academic Unit: Pharmacology and Toxicology (EMSOP)
Language: English
Resource Type: Journal article
Identifiers: 991031654656204646